PMID: 28631573
(None)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Effects of miR-1236-3p and miR-370-5p on activation of p21 in various tumors and its inhibition on the growth of lung cancer cells .
1 The mechanism of dsRNA -induced gene activation (RNAa) is being gradually unveiled .
2 The plentiful evidence that it existed in mammalian species other than human demonstrated that dsRNA -mediated RNAa is a conservative phenomenon .
3 Simultaneously , accumulating evidence suggested that microRNAs could activate gene expression by targeting promoter .
4 Nevertheless , it is ambiguous whether microRNA -induced gene activation in different human cells is a common phenomenon .
5 The study we performed verified that miR-1236-3p ( miR-1236 ) and miR-370-5p can activate p21 expression in bladder cancer ( BCa ) T24 , EJ cells , and non-small - cell lung carcinoma A549 cells , while in hepatocellular HepG2 cells both microRNAs cannot effectively induce the expression of P21WAF1/CIP1 ( p21 ) .
6 In pancreatic cancer PANC-1 cells , only miR-370-5p had the potent abilities to induce p21 expression rather than miR-1236-3p .
7 Unlike microRNA -mediated RNA activation , we can observe that dsP21-322 significantly activated p21 in above cells .
8 Besides , we demonstrated that miR-1236 and miR-370 inhibited cyclin D1-CDK4/CDK6 pathway while upregulated E-cadherin expression by upregulation of p21 .
9 Overexpression of these two microRNAs in A549 induced cell -cycle arrest and cell senescence , delayed cell proliferation and colony formation , and inhibited migration and invasion .
10 In conclusion , microRNA -mediated RNAa depends on the cell context , and miR-1236 and miR-370 can inhibit non-small - cell lung carcinoma cell growth by upregulating p21 expression in vitro .



PMID: 28322158
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Effect and mechanism of curcumin on EZH2 - miR-101 regulatory feedback loop in multiple myeloma .
1 BACKGROUND :
2 Multiple myeloma is the second most prevalent hematologic malignancy and thought to be incurable .
3 Therefore , it's urgent to find new drugs for treatment .
4 Some experiments have shown that curcumin might have great potential in treating multiple myeloma , while the mechanism is still unknown .
5 EZH2 and SUZ12 are the core proteins in PRC2 and their expression are increased in various human cancers , including the poor prognostic multiple myeloma .
6 Meanwhile , the regulation of miRNAs and EZH2 has been demonstrated in other cancer researches , like lung cancer , pancreatic cancer , leukemia and so on .
7 OBJECTIVE :
8 To reveal the mechanism behind the anti-tumor effect of cucurmin in multiple myeloma .
9 METHOD :
10 The effect of curcumin on the growth of MM cells was studied by MTT assay in the MM cell lines RPMI8226 and U266 .
11 Apoptosis was measured by Annexin V-FITC/PI double staining method .
12 Western blotting , RT-PCR and luciferase activity assay were used to assess the expression of EZH2 , SUZ12 , miR-101 and down-stream proteins such as E-cadherin , MMP9 , c-Myc , cyclin D3 , CDK4 and CDK6 .
13 RESULTS :
14 Curcumin could significantly inhibite the proliferation of MM cells in a time - and concentration -dependent manner .
15 Curcumin induced apoptosis by inhibiting the expression of EZH2 , and the apoptosis rates were 16.42% and 25.62% when the RPMI8226 cells incubated with 5 and 10 mumol/L of curcumin .
16 For U266 cells , the apoptosis rates were 15.25% and 21.28% .
17 The up-regulation of miR-101 led to the lower expression of EZH2 .
18 In adverse , the expression of EZH2 induced lower expression of miR-101 .
19 The down-stream proteins of miR-101 were regulated by curcumin and EZH2 at the same time .
20 CONCLUSION :
21 Our experiments verified that the effect and mechanism of curcumin on multiple myeloma is via EZH2 - miR-101 regulatory feedback loop , which would lead us to a new way of investigating multiple myeloma and come up with new therapies in treating the disease .



PMID: 27840954
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Identfication of key miRNAs in pancreatitis using bioinformatics analysis of microarray data .
1 Pancreatitis is a type of inflammation in the pancreas , which frequently occurs due to alcohol and gallstones .
2 The present study aimed to identify pancreatitisassociated microRNAs ( miRNAs ) by analyzing the microarray of GSE24279 .
3 GSE24279 was downloaded from the Gene Expression Omnibus , composed of a collective of 27 pancreatitis and 22 normal control samples .
4 The differentially expressed miRNAs ( DEmiRNAs ) in pancreatitis samples were screened using the Limma package in Bioconductor .
5 Subsequently , target genes of the DEmiRNAs were predicted using the miRecords and miRWalk databases .
6 Their potential functions were analyzed by functional and pathway enrichment analysis using the Database for Annotation , Visualization and Integrated Discovery online tool .
7 Finally , pancreatitisassociated genes among the target genes identified were searched using the Comparative Toxicogenomics Database , and a regulatory network of pancreatitisassociated genes and their target miRNAs were constructed using Cytoscape software .
8 A total 14 upregulated and 39 downregulated miRNAs were identified in pancreatitis samples compared with control samples and 290 target genes of DEmiRNAs were determined .
9 Cyclin D1 ( CCND1 ) , vakt murine thymoma viral oncogene homolog 2 ( AKT2 ) , cyclindependent kinase 6 ( CDK6 ) and SMAD family member 2 ( SMAD2 ) were involved in the pathway of pancreatic cancer .
10 Among the target genes , 279 genes were pancreatitisassociated genes , which in turn were targeted by 37 miRNAs in the regulatory network .
11 HsamiR15a , hsamiR16 , hsamiR155 , hsamiR375 and hsamiR429 in particular may be involved in pancreatitis by targeting genes in the regulatory network , including hsamiR15a-->CCND1 , hsamiR16-->CCND1 , hsamiR155-->CCND1/SMAD2 , hsamiR375-->AKT2/CDK6 and hsamiR429-->CCND1 .
12 The above miRNAs and their targets may contribute to the pathogenesis of pancreatitis ; therefore , they may be potential therapeutic targets .



PMID: 27354587
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 1alpha,25 ( OH ) 2D3 Analog , MART-10 , Inhibits Neuroendocrine Tumor Cell Growth Through Induction of G0/G1 Cell -cycle Arrest and Apoptosis .
1 BACKGROUND :
2 Neuroendocrine tumors ( NETs ) are the second most common digestive malignancy .
3 For advanced NETs , survival is not satisfactory .
4 Vitamin D has emerged as a promising anticancer drug .
5 MATERIALS AND METHODS :
6 Cell proliferation assay , western blot , flow cytometry , and terminal deoxynucleotidyl transferase dUTP nick-end labeling ( TUNEL ) assays were applied .
7 RESULTS :
8 Μ We demonstrated that RIN-m cells , neuroendocrine tumor cells , expressed vitamin D receptor ( VDR ) and VDR expression increased with increasing exposure to 1alpha,25-dihydroxyvitamin D3 [1alpha,25 (OH) 2D3] or MART-10 , a 1alpha,25 ( OH ) 2D3 analog .
9 MART-10 had anti-growth effect on RIN-m cells comparable to those of 1alpha,25 ( OH ) 2D3 The growth inhibition of both drugs was mediated by induction of cell -cycle arrest at G0/G1 phase and apoptosis .
10 Western blot assay further revealed that this G0/G1 arrest was due to the up-regulation of p27 and down-regulation of cyclin dependent kinase 4 ( CDK4 ) , with MART-10 also reducing CDK6 .
11 Apoptosis induction was further supported by increased cleaved caspase-3 expression after treatment .
12 CONCLUSION :
13 MART-10 appears to be a promising regimen for NET treatment .



PMID: 27267120
(None)  
Terms: , mouse model, mouse, mouse models, mice
Sent# Symbols Sentence Mnemonics
0 SAHA -induced loss of tumor suppressor Pten gene promotes thyroid carcinogenesis in a mouse model .
1 Thyroid cancer is on the rise .
2 Novel approaches are needed to improve the outcome of patients with recurrent and advanced metastatic thyroid cancers .
3 FDA approval of suberoylanilide hydroxamic acid ( SAHA ; vorinostat ) , an inhibitor of histone deacetylase , for the treatment of hematological malignancies led to the clinical trials of vorinostat for advanced thyroid cancer .
4 However , patients were resistant to vorinostat treatment .
5 To understand the molecular basis of resistance , we tested the efficacy of SAHA in two mouse models of metastatic follicular thyroid cancer : Thrb ( PV/PV ) and Thrb ( PV/PV ) Pten(+/-) mice .
6 In both , thyroid cancer is driven by overactivation of PI3K-AKT signaling .
7 However , the latter exhibit more aggressive cancer progression due to haplodeficiency of the tumor suppressor , the Pten gene .
8 SAHA had no effects on thyroid cancer progression in Thrb ( PV/PV ) mice , indicative of resistance to SAHA .
9 Unexpectedly , thyroid cancer progressed in SAHA-treated Thrb (PV/PV) Pten(+/-) mice with accelerated occurrence of vascular invasion , anaplastic foci , and lung metastasis .
10 Molecular analyses showed further activated PI3K-AKT in thyroid tumors of SAHA-treated Thrb (PV/PV) Pten(+/-) mice , resulting in the activated effectors , p-Rb , CDK6 , p21 ( Cip1 ) , p-cSrc , ezrin , and matrix metalloproteinases , to increase proliferation and invasion of tumor cells .
11 Single-molecule DNA analysis indicated that the wild-type allele of the Pten gene was progressively lost , whereas carcinogenesis progressed in SAHA-treated Thrb (PV/PV) Pten(+/-) mice .
12 Thus , this study has uncovered a novel mechanism by which SAHA -induced loss of the tumor suppressor Pten gene to promote thyroid cancer progression .
13 Effectors downstream of the Pten loss-induced signaling may be potential targets to overcome resistance of thyroid cancer to SAHA .



PMID: 26823495
(Cell)  
Terms: xenograft, mouse, genetically engineered mouse, mouse model, mice
Sent# Symbols Sentence Mnemonics
0 GSK-3beta Governs Inflammation-Induced NFATc2 Signaling Hubs to Promote Pancreatic Cancer Progression .
1 We aimed to investigate the mechanistic , functional , and therapeutic role of glycogen synthase kinase 3beta ( GSK-3beta ) in the regulation and activation of the proinflammatory oncogenic transcription factor nuclear factor of activated T cells ( NFATc2 ) in pancreatic cancer .
2 IHC , qPCR , immunoblotting , immunofluorescence microscopy , and proliferation assays were used to analyze mouse and human tissues and cell lines .
3 Protein - protein interactions and promoter regulation were analyzed by coimmunoprecipitation , DNA pulldown , reporter , and ChIP assays .
4 Preclinical assays were performed using a variety of pancreatic cancer cells lines , xenografts , and a genetically engineered mouse model ( GEMM ) .
5 GSK-3beta -dependent SP2 phosphorylation mediates NFATc2 protein stability in the nucleus of pancreatic cancer cells stimulating pancreatic cancer growth .
6 In addition to protein stabilization , GSK-3beta also maintains NFATc2 activation through a distinct mechanism involving stabilization of NFATc2-STAT3 complexes independent of SP2 phosphorylation .
7 For NFATc2-STAT3 complex formation , GSK-3beta -mediated phosphorylation of STAT3 at Y705 is required to stimulate euchromatin formation of NFAT target promoters , such as cyclin -dependent kinase -6 , which promotes tumor growth .
8 Finally , preclinical experiments suggest that targeting the NFATc2-STAT3-GSK-3beta module inhibits proliferation and tumor growth and interferes with inflammation-induced pancreatic cancer progression in Kras ( G12D ) mice .
9 In conclusion , we describe a novel mechanism by which GSK-3beta fine-tunes NFATc2 and STAT3 transcriptional networks to integrate upstream signaling events that govern pancreatic cancer progression and growth .
10 Furthermore , the therapeutic potential of GSK-3beta is demonstrated for the first time in a relevant Kras and inflammation-induced GEMM for pancreatic cancer .



PMID: 26552408
(None)  
Terms: , mouse model, mouse, mice
Sent# Symbols Sentence Mnemonics
0 Inhibition of STAT3 activity delays obesity-induced thyroid carcinogenesis in a mouse model .
1 Compelling epidemiologic studies indicate that obesity is a risk factor for many human cancers , including thyroid cancer .
2 In recent decades , the incidence of thyroid cancer has dramatically increased along with a marked rise in obesity prevalence .
3 Μ We previously demonstrated that a high fat diet ( HFD ) effectively induced the obese phenotype in a mouse model of thyroid cancer ( Thrb ( PV/PV ) Pten(+/-) mice ) .
4 Moreover , HFD activates the STAT3 signal pathway to promote more aggressive tumor phenotypes .
5 ✓ The aim of the present study was to evaluate the effect of S3I-201 , a specific inhibitor of STAT3 activity , on HFD -induced aggressive cancer progression in the mouse model of thyroid cancer . GM-INV-RO
6 WT and Thrb ( PV/PV ) Pten(+/-) mice were treated with HFD together with S3I-201 or vehicle-only as controls .
7 We assessed the effects of S3I-201 on HFD -induced thyroid cancer progression , the leptin-JAK2-STAT3 signaling pathway , and key regulators of epithelial-mesenchymal transition ( EMT ) .
8 S3I-201 effectively inhibited HFD -induced aberrant activation of STAT3 and its downstream targets to markedly inhibit thyroid tumor growth and to prolong survival .
9 Decreased protein levels of cyclins D1 and B1 , cyclin dependent kinase 4 ( CDK4 ) , CDK6 , and phosphorylated retinoblastoma protein led to the inhibition of tumor cell proliferation in S3I-201-treated Thrb (PV/PV) Pten(+/-) mice .
10 Reduced occurrence of vascular invasion and blocking of anaplasia and lung metastasis in thyroid tumors of S3I-201-treated Thrb (PV/PV) Pten(+/-) mice were mediated via decreased expression of vimentin and matrix metalloproteinases , two key effectors of EMT .
11 The present findings suggest that inhibition of the STAT3 activity would be a novel treatment strategy for obesity-induced thyroid cancer .



PMID: 26530532
(Patient)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 ✓ Elevated GRP78 expression is associated with poor prognosis in patients with pancreatic cancer . GE-ASS-RO
1 Glucose-regulated protein 78 ( GRP78 ) is a member of the heat-shock protein 70 family .
2 We evaluated the expression of GRP78 using tissue microarray-based immunohistochemistry in tumor tissues and adjacent nontumor tissues from 180 pancreatic ductal adenocarcinoma ( PDAC ) patients .
3 The associations between the expression levels of GRP78 , clinicopathological factors , and overall survival were evaluated .
4 Μ The results showed that the expression of GRP78 was significantly higher in PDAC cells than in normal pancreatic duct cells within adjacent nontumor tissues ( p <005 ) .
5 The increased expression of GRP78 in the tumor tissues was significantly correlated with a higher T-stage ( p <005 ) and a shorter overall survival ( OS , p <005 ) .
6 In an in vitro study , the regulation of GRP78 in the PDAC cell lines affected the proliferation , migration , and invasion of PDAC cells through the regulation of CyclinD1 , cyclin-dependent kinase ( CDK ) 4 , CDK6 , phospho-signal transducer , activator of transcription 3 ( p-STAT3 ) , janus kinase 2 ( JAK2 ) , ras homolog gene family member A ( RhoA ) , Rho-associated kinase 1 ( ROCK1 ) , and sterile alpha motif domain containing protein 4 ( Smad4 ) .
7 The present data suggest that GRP78 plays a crucial role in the proliferation , migration , and invasion of pancreatic cancer cells and may be a suitable prognostic marker in PDAC .



PMID: 26516023
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Ferulic acid decreases cell viability and colony formation while inhibiting migration of MIA PaCa-2 human pancreatic cancer cells in vitro .
1 Novel and combinatorial treatment methods are becoming sought after entities in cancer treatment and these treatments are even more valuable for pancreatic cancer .
2 The scientists are always on the lookout for new chemicals to help them in their fight against cancer .
3 In this study , we examine the effects of ferulic acid ( FA ) , a phenolic compound , on gene expression , viability , colony formation and migration/invasion in the cultured MIA PaCa-2 human pancreatic cancer cell .
4 Cytotoxic effects of FA were determined by using trypan blue dye exclusion test and Cell TiterGlo ( CTG ) assay .
5 IC50 dose in MIA PaCa-2 cells was detected as 500muM/ml at the 72nd hour .
6 Expression profiles of certain cell cycle and apoptosis genes such as CCND1 ( cyclin D1 ) , CDK4 , CDK6 , RB , p21 , p16 , p53 , caspase-3 , caspase-9 , caspase-8 , caspase-10 , Bcl-2 , BCL-XL , BID , DR4 , DR5 , FADD , TRADD , PARP , APAF , Bax , Akt , PTEN , PUMA , NOXA , MMP2 , MMP9 , TIMP1 and TIMP2 were determined by real-time PCR .
7 The effect of FA on cell viability was determined by CellTiter-Glo(R) Luminescent Cell Viability Assay .
8 Additionally , effects of FA on colony formation and invasion were also investigated .
9 Μ It was observed that FA caused a significant decrease in the expression of CCND1 , CDK 4/6 , Bcl2 and caspase 8 and 10 in the MIA PaCa-2 cells while causing an increase in the expression of p53 , Bax , PTEN caspase 3 and 9 .
10 FA was observed to decrease colony formation while inhibiting cell invasion and migration as observed by the BioCoat Matrigel Invasion Chamber guide and colony formation assays .
11 In conclusion , FA is thought to behave as an anti-cancer agent by affecting cell cycle , apoptotic , invasion and colony formation behavior of MIA PaCa-2 cells .
12 Therefore , FA is placed as a strong candidate for further studies aimed at finding a better , more effective treatment approach for pancreatic cancer .



PMID: 26500333
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets .
1 AIM :
2 Μ We queried whether extrahepatic cholangiocarcinoma featured clinically relevant genomic alterations that could lead to targeted therapy .
3 METHODS :
4 Comprehensive genomic profiling by hybridisation capture of up to 315 genes was performed on 99 clinically advanced extrahepatic cholangiocarcinoma .
5 RESULTS :
6 There were 60 male and 39 female patients with a median age of 60.5 years .
7 Μ A total of 400 alterations were identified ( mean 40 ; range 0-13 ) in 84 genes .
8 Μ Eighty-two ( 83% ) of extrahepatic cholangiocarcinoma patients featured atleast one clinically relevant genomic alterations including KRAS ( 43% ) ; ERBB2 ( 9% ) , PTEN ( 7% ) ; ATM and NF1 ( 6% ) and CCND1 , FBXW7 , GNAS , MDM2 and NRAS ( all at 5% ) .
9 Μ BRAF , BRCA2 , CDK4 , CDK6 , FGFR1 , FGFR3 , PTCH1 , RAF1 and STK11 were each altered in a single patient .
10 Μ No IDH1/2 mutations or FGFR2 gene fusions were identified .
11 CONCLUSIONS :
12   Comprehensive genomic profiling of extrahepatic cholangiocarcinoma differs significantly from intrahepatic cholangiocarcinoma and pancreatic adenocarcinoma , and reveals diverse opportunities for the use of targeted therapies .



PMID: 26334619
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Anti-proliferative and anti-invasive effects of ferulic acid in TT medullary thyroid cancer cells interacting with URG4/URGCP .
1 Ferulic acid ( 4-hydroxy-3-methoxycinnamic acid ; FA ) , a common dietary plant phenolic compound , is abundant in fruits and vegetables .
2 The aim of present study is to investigate the effects of FA on cell cycle , apoptosis , invasion , migration , and colony formation in the TT medullary thyroid cancer cell line .
3 The effect of FA on cell viability was determined by using CellTiter-Glo assay .
4 IC50 dose in the TT cells was detected as 150 muM .
5 URG4/URGCP ( upregulated gene-4/upregulator of cell proliferation ) is a novel gene in full-length mRNA of 3.607 kb located on 7p13 .
6 It was determined that FA caused a decrease in the expression of novel gene URG4/URGCP , CCND1 , CDK4 , CDK6 , BCL2 , MMP2 , and MMP9 , a significant increase in the expression of p53 , PARP , PUMA , NOXA , BAX , BID , CASP3 , CASP9 , and TIMP1 genes in TT human thyroid cancer cell line by using real-time PCR .
7 It was found that FA in TT cells suppressed invasion , migration , and colony formation by using matrigel invasion chamber , wound healing , and colony formation assay , respectively .
8 In conclusion , it is thought that FA indicates anticarcinogenesis activity by affecting cell cycle arrest , apoptosis , invasion , migration , and colony formation on TT cells .



PMID: 26045769
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Downregulation of NUF2 inhibits tumor growth and induces apoptosis by regulating lncRNA AF339813 .
1 Recent studies have shown that NUF2 ( Ndc80 kinetochore complex component ) play important roles in multiple human cancers .
2 In our previous report , NUF2 expression was stronger in tumor tissues than in normal pancreatic tissues .
3 However , whether and how NUF2 play a role in pancreatic cancer progression remains largely unknown .
4 The aim of our study is to investigate the expression and functional role of NUF2 in human PC .
5 NUF2 expression was measured in 10 pairs of PC cancerous and noncancerous tissue samples by quantitative real-time PCR .
6 The effects of NUF2 on PC cells were studied by RNA interference .
7 Apoptosis and cell cycle were analyzed by flow cytometry .
8 Cells viability was evaluated using MTT .
9 CDK4/CDK6 activity was measured by Western blot assay .
10 LncRNAs regulated by NUF2 were gained from bioinformatics analysis .
11 The role of LncRNA AF339813 , regulated by NUF2 , was finally characterized in PC cells by siRNA .
12 Our results showed that NUF2 mRNA and protein were significantly overexpressed in Human PC tissues and several PC cell lines .
13 Through bioinformatics analysis and knockdown NUF2 in PC cells , we found LncRNA AF339813 was positively regulated by NUF2 .
14 We further demonstrated that knockdown of AF339813 by siRNA in PC cells significantly reduced cell proliferation and promoted apoptosis .
15 Thus , we conclude that NUF2 is consistently overexpressed in human PC and NUF2 is closely linked with human PC progression through the meditator LncRNA AF339813 .
16 Our studies may contribute to understand the molecular mechanism of PC pathogenesis and clinical therapy .



PMID: 26008974
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Identification of deregulation of apoptosis and cell cycle in neuroendocrine tumors of the lung via NanoString nCounter expression analysis .
1 BACKGROUND :
2 Neuroendocrine tumors of the lung comprise typical ( TC ) and atypical carcinoids ( AC ) , large-cell neuroendocrine cancer ( LCNEC ) and small-cell lung cancer ( SCLC ) .
3 Cell cycle and apoptosis are key pathways of multicellular homeostasis and deregulation of these pathways is associated with cancerogenesis .
4 MATERIALS AND METHODS :
5 Sixty representative FFPE-specimens ( 16 TC , 13 AC , 16 LCNEC and 15 SCLC ) were used for mRNA expression analysis using the NanoString technique .
6 Eight genes related to apoptosis and ten genes regulating key points of cell cycle were investigated .
7 RESULTS :
8 Μ ASCL1 , BCL2 , CASP8 , CCNE1 , CDK1 , CDK2 , CDKN1A and CDKN2A showed lower expression in carcinoids compared to carcinomas .
9 Μ In contrast , CCNE1 and CDK6 showed elevated expression in carcinoids compared to carcinomas .
10 The calculated BCL2/BAX ratio showed increasing values from TC to SCLC .
11 Between SCLC and LCNEC CDK2 , CDKN1B , CDKN2A and PNN expression was significantly different with higher expression in SCLC .
12 CONCLUSION :
13 Carcinoids have increased CDK4/6 and CCND1 expression controlling RB1 phosphorylation via this signaling cascade .
14 CDK2 and CCNE1 were increased in carcinomas showing that these use the opposite way to control RB1 .
15 BAX and BCL2 are antagonists in regulating apoptosis .
16 BCL2 expression increased over BAX expression with increasing malignancy of the tumor from TC to SCLC .



PMID: 25971967
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Transient Receptor Potential Canonical 1 ( TRPC1 ) Channels as Regulators of Sphingolipid and VEGF Receptor Expression : IMPLICATIONS FOR THYROID CANCER CELL MIGRATION AND PROLIFERATION .
1 The identity of calcium channels in the thyroid is unclear .
2 In human follicular thyroid ML-1 cancer cells , sphingolipid sphingosine 1-phosphate ( S1P ) , through S1P receptors 1 and 3 ( S1P1/S1P3 ) , and VEGF receptor 2 ( VEGFR2 ) stimulates migration .
3 We show that human thyroid cells express several forms of transient receptor potential canonical ( TRPC ) channels , including TRPC1 .
4 In TRPC1 knockdown ( TRPC1-KD ) ML-1 cells , the basal and S1P-evoked invasion and migration was attenuated .
5 Furthermore , the expression of S1P3 and VEGFR2 was significantly down-regulated .
6 Transfecting wild-type ML-1 cells with a nonconducting TRPC1 mutant decreased S1P3 and VEGFR2 expression .
7 In TRPC1-KD cells , receptor -operated calcium entry was decreased .
8 To investigate whether the decreased receptor expression was due to attenuated calcium entry , cells were incubated with the calcium chelator BAPTA-AM ( 1,2-bis ( o-aminophenoxy ) ethane-N , N , N' , N'-tetraacetic acid ) .
9 In these cells , and in cells where calmodulin and calmodulin -dependent kinase were blocked pharmacologically , S1P3 and VEGFR2 expression was decreased .
10 In TRPC1-KD cells , both hypoxia-inducible factor 1alpha expression and the secretion and activity of MMP2 and MMP9 were attenuated , and proliferation was decreased in TRPC1-KD cells .
11 This was due to a prolonged G1 phase of the cell cycle , a significant increase in the expression of the cyclin -dependent kinase inhibitors p21 and p27 , and a decrease in the expression of cyclin D2 , cyclin D3 , and CDK6 .
12 Transfecting TRPC1 to TRPC1-KD cells rescued receptor expression , migration , and proliferation .
13 Thus , the expression of S1P3 and VEGFR2 is mediated by a calcium -dependent mechanism .
14 TRPC1 has a crucial role in this process .
15 This regulation is important for the invasion , migration , and proliferation of thyroid cancer cells .



PMID: 25719666
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Whole genomes redefine the mutational landscape of pancreatic cancer .
1 Pancreatic cancer remains one of the most lethal of malignancies and a major health burden .
2 We performed whole - genome sequencing and copy number variation ( CNV ) analysis of 100 pancreatic ductal adenocarcinomas ( PDACs ) .
3 Chromosomal rearrangements leading to gene disruption were prevalent , affecting genes known to be important in pancreatic cancer ( TP53 , SMAD4 , CDKN2A , ARID1A and ROBO2 ) and new candidate drivers of pancreatic carcinogenesis ( KDM6A and PREX2 ) .
4 Patterns of structural variation ( variation in chromosomal structure ) classified PDACs into 4 subtypes with potential clinical utility : the subtypes were termed stable , locally rearranged , scattered and unstable .
5 Μ A significant proportion harboured focal amplifications , many of which contained druggable oncogenes ( ERBB2 , MET , FGFR1 , CDK6 , PIK3R3 and PIK3CA ) , but at low individual patient prevalence .
6 Genomic instability co-segregated with inactivation of DNA maintenance genes ( BRCA1 , BRCA2 or PALB2 ) and a mutational signature of DNA damage repair deficiency .
7   Of 8 patients who received platinum therapy , 4 of 5 individuals with these measures of defective DNA maintenance responded .



PMID: 25157181
(None)  
Terms: , mice
Sent# Symbols Sentence Mnemonics
0 Cdk4 and Cdk6 cooperate in counteracting the INK4 family of inhibitors during murine leukemogenesis .
1 Cdk4 and Cdk6 are related protein kinases that bind d-type cyclins and regulate cell -cycle progression .
2 Cdk4/6 inhibitors are currently being used in advanced clinical trials and show great promise against many types of tumors .
3 Cdk4 and Cdk6 are inhibited by INK4 proteins , which exert tumor-suppressing functions .
4 To test the significance of this inhibitory mechanism , we generated knock-in mice that express a Cdk6 mutant (Cdk6 R31C) insensitive to INK4 -mediated inhibition .
5 Cdk6 (R/R) mice display altered development of the hematopoietic system without enhanced tumor susceptibility , either in the presence or absence of p53 .
6 Unexpectedly , Cdk6 R31C impairs the potential of hematopoietic progenitors to repopulate upon adoptive transfer or after 5-fluorouracil -induced damage .
7 The defects are overcome by eliminating sensitivity of cells to INK4 inhibitors by introducing the INK4-insensitive Cdk4 R24C allele , and INK4-resistant mice are more susceptible to hematopoietic and endocrine tumors .
8 ✓ In BCR-ABL -transformed hematopoietic cells , Cdk6 R31C causes increased binding of p16 ( INK4a ) to wild-type Cdk4 , whereas cells harboring Cdk4 R24C and Cdk6 R31C are fully insensitive to INK4 inhibitors , resulting in accelerated disease onset .
9 Our observations reveal that Cdk4 and Cdk6 cooperate in hematopoietic tumor development and suggest a role for Cdk6 in sequestering INK4 proteins away from Cdk4 .



PMID: 25050737
(Cell)  
Terms: xenograft, mice
Sent# Symbols Sentence Mnemonics
0 Rottlerin suppresses growth of human pancreatic tumors in nude mice , and pancreatic cancer cells isolated from Kras ( G12D ) mice .
1 The purpose of the study was to examine the molecular mechanisms by which rottlerin inhibited growth of human pancreatic tumors in Balb C nude mice , and pancreatic cancer cells isolated from Kras ( G12D ) mice .
2 AsPC-1 cells were injected subcutaneously into Balb c nude mice , and tumor-bearing mice were treated with rottlerin .
3 Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining , respectively .
4 The expression of components of Akt , Notch , and Sonic Hedgehog ( Shh ) pathways were measured by the immunohistochemistry , Western blot analysis , and/or q-RT-PCR .
5 The effects of rottlerin on pancreatic cancer cells isolated from Kras ( G12D ) mice were also examined .
6 Rottlerin-treated mice showed a significant inhibition in tumor growth which was associated with suppression of cell proliferation , activation of capase-3 and cleavage of PARP .
7 Rottlerin inhibited the expression of Bcl-2 , cyclin D1 , CDK2 and CDK6 , and induced the expression of Bax in tumor tissues compared to untreated control .
8 Rottlerin inhibited the markers of angiogenesis ( Cox-2 , VEGF , VEGFR , and IL-8 ) , and metastasis ( MMP-2 and MMP-9 ) , thus blocking production of tumorigenic mediators in tumor microenvironment .
9 Rottlerin also inhibited epithelial-mesenchymal transition by up-regulating E-cadherin and inhibiting the expression of Slug and Snail .
10   Furthermore , rottlerin treatment of xenografted tumors or pancreatic cancer cells isolated from Kras ( G12D ) mice showed a significant inhibition in Akt , Shh and Notch pathways compared to control groups .
11 These data suggest that rottlerin can inhibit pancreatic cancer growth by suppressing multiple signaling pathways which are constitutively active in pancreatic cancer .
12   Taken together , our data show that the rottlerin induces apoptosis and inhibits pancreatic cancer growth by targeting Akt , Notch and Shh signaling pathways , and provide a new therapeutic approach with translational potential for humans .



PMID: 24959213
(Cell)  
Terms: in vivo, tumor model
Sent# Symbols Sentence Mnemonics
0 High expression of erythropoietin-producing hepatoma cell line -B2 ( EphB2 ) predicts the efficiency of the Qingyihuaji formula treatment in pancreatic cancer CFPAC-1 cells through the EphrinB1-EphB2 pathway .
1 Μ Our previous study demonstrated that inhibition of erythropoietin-producing hepatoma cell line -B2 ( EphB2 ) expression resulted in the promotion of cancer growth , with EphB2 acting as a tumor suppressor in pancreatic cancer .
2   Qingyihuaji formula ( QYHJ ) , a traditional Chinese medicine , acts as an independent protective factor for pancreatic cancer patient survival and different patients have shown various responses to QYHJ treatment .
3 In the current study , the different effects on tumor growth inhibition following QYHJ treatment in cells with different levels of EphB2 expression were investigated to reveal the mechanism .
4 A subcutaneously transplanted tumor model using cancer cells with different levels of EphB2 expression were established in vivo and received a four-week QYHJ intervention .
5 Tumor weight inhibitory rate and tumor volume deflation were evaluated .
6 The cell cycle and apoptosis were analyzed by flow cytometry , and reverse transcription polymerase chain reaction and western blot analysis were used to assess mRNA and protein levels .
7 The results showed that the tumor weight inhibitory rate was 31.40 , 31.33 and 18.36% in CFPAC-1 , CFPAC-1 control RNAi and CFPAC-1 EphB2 RNAi cells following QYHJ treatment , respectively .
8 A statistically significant difference was identified in CFPAC-1 ( P<005 ) and CFPAC-1 control RNAi ( P<001 ) cells .
9 In addition , a statistically significant increase was identified in the G0/G1 phase population ( P<005 ) and a statistically significant decrease was identified in the S phase population ( P<005 ) in CFPAC-1 and CFPAC-1 control RNAi cells ; however , no significant difference was identified in the CFPAC-1 EphB2 RNAi cells following QYHJ treatment .
10 QYHJ upregulated the mRNA and protein level of Eph receptor-interacting B1 ( EphrinB1 ) in the cells that were expressing different levels of EphB2 , however , QYHJ did not regulate EphB2 expression .
11 In CFPAC-1 and CFPAC-1 control RNAi cells , the QYHJ treatment resulted in a statistically significant decrease in cyclin-dependent kinase 6 ( CDK6 ) mRNA ( P<005 ) and protein ( P<005 ) levels .
12 The high expression of EphB2 predicted the superior response rate to the QYHJ treatment through a mechanism of inhibiting the cell cycle by an EphrinB1-EphB2 -induced CDK6 decrease in CFPAC-1 cells .
13 Therefore , EphB2 acts as a predictive factor for QYHJ treatment in pancreatic cancer CFPAC-1 cells .



PMID: 24694877
(Cell)  
Terms: xenograft, in vitro, mice, transgenic mice
Sent# Symbols Sentence Mnemonics
0 Embelin suppresses growth of human pancreatic cancer xenografts , and pancreatic cancer cells isolated from KrasG12D mice by inhibiting Akt and Sonic hedgehog pathways .
1 Pancreatic cancer is a deadly disease , and therefore effective treatment and/or prevention strategies are urgently needed .
2 The objectives of this study were to examine the molecular mechanisms by which embelin inhibited human pancreatic cancer cell growth in vitro , and xenografts in Balb C nude mice , and pancreatic cancer cell growth isolated from KrasG12D transgenic mice .
3 XTT assays were performed to measure cell viability .
4 AsPC-1 cells were injected subcutaneously into Balb c nude mice and treated with embelin .
5 Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining , respectively .
6 The expression of Akt , and Sonic Hedgehog ( Shh ) and their target gene products were measured by the immunohistochemistry , and Western blot analysis .
7 The effects of embelin on pancreatic cancer cells isolated from 10-months old KrasG12D mice were also examined .
8 Embelin inhibited cell viability in pancreatic cancer AsPC-1 , PANC-1 , MIA PaCa-2 and Hs 766T cell lines , and these inhibitory effects were blocked either by constitutively active Akt or Shh protein .
9 Embelin-treated mice showed significant inhibition in tumor growth which was associated with reduced expression of markers of cell proliferation ( Ki67 , PCNA and Bcl-2 ) and cell cycle ( cyclin D1 , CDK2 , and CDK6 ) , and induction of apoptosis ( activation of caspase-3 and cleavage of PARP , and increased expression of Bax ) .
10 In addition , embelin inhibited the expression of markers of angiogenesis ( COX-2 , VEGF , VEGFR , and IL-8 ) , and metastasis ( MMP-2 and MMP-9 ) in tumor tissues .
11 Antitumor activity of embelin was associated with inhibition of Akt and Shh pathways in xenografts , and pancreatic cancer cells isolated from KrasG12D mice .
12 Furthermore , embelin also inhibited epithelial-to-mesenchymal transition ( EMT ) by up-regulating E-cadherin and inhibiting the expression of Snail , Slug , and ZEB1 .
13 These data suggest that embelin can inhibit pancreatic cancer growth , angiogenesis and metastasis by suppressing Akt and Shh pathways , and can be developed for the treatment and/or prevention of pancreatic cancer .



PMID: 24389175
(None)  
Terms: , mice
Sent# Symbols Sentence Mnemonics
0 Embelin suppresses pancreatic cancer growth by modulating tumor immune microenvironment .
1 Since pancreatic carcinoma is largely refractory to conventional therapies , development of novel agents is required for the effective treatment of pancreatic cancer .
2 The objective of this paper was to examine the molecular mechanisms by which embelin inhibited human pancreatic cancer growth in mice by modulating tumor immune microenvironment .
3 Embelin inhibited PANC-1 tumor growth , angiogenesis , and metastasis which were associated with suppression of Akt and Sonic Hedgehog ( Shh ) pathways .
4 Embelin inhibited the expression of Bcl-2 , cyclin D1 , CDK2 and CDK6 , IL-6 and IL-8 , and induced the expression of Bax in tumor tissues .
5 Embelin also reversed epithelial-mesenchymal transition by up-regulating E-cadherin and inhibiting the expression of Snail , Slug and Zeb1 .
6 Embelin inhibited pancreatic cancer growth in Kras ( G12D ) mice by modulating tumor immune microenvironment where CTL , NKT , gammadeltaT , NK , and IFNgamma ( Th1 type ) cells were up-regulated , and Th17 , PMN-MDSC , IL-6 and IL-8 ( Th2 type ) immune cells were inhibited .
7 These data suggest that embelin can inhibit pancreatic cancer growth by modulating tumor immune microenvironment and Akt and Shh pathways , and inhibiting inflammation .
8   Embelin may offer therapeutic benefits for the treatment and/or prevention of pancreatic cancer .



PMID: 24026436
(Cell)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 Downregulation of gas5 increases pancreatic cancer cell proliferation by regulating CDK6 .
1 Μ Recent studies have revealed that long non-coding RNAs ( lncRNAs ) play important roles in cancer biology and that lncRNA gas5 ( growth arrest-specific 5 ) regulates breast cancer cell growth .
2 However , the role of gas5 in pancreatic cancer progression remains largely unknown .
3 In the current study , we assay the expression level of gas5 in pancreatic cancer tissues and define the role of gas5 in the regulation of pancreatic cancer cell proliferation .
4 We verify that the expression level of gas5 is significantly decreased in pancreatic cancer tissues compared with normal control .
5 Overexpression of gas5 in pancreatic cancer cells inhibits cell proliferation , whereas gas5 inhibition induces a significant decrease in G0/G1 phase and an increase in S phase .
6 We further demonstrate that gas5 negatively regulates CDK6 ( cyclin-dependent kinase 6 ) expression in vitro and in vivo .
7 More importantly , knockdown of CDK6 partially abrogates gas5-siRNA-induced cell proliferation .
8   These data suggest an important role of gas5 in the molecular etiology of pancreatic cancer and implicate the potential application of gas5 in pancreatic cancer therapy .



PMID: 23684930
(None)  
Terms: xenograft, mice
Sent# Symbols Sentence Mnemonics
0 Ellagic acid inhibits human pancreatic cancer growth in Balb c nude mice .
1 Ellagic acid ( EA ) is a polyphenol found in several plants and fruits .
2 The objectives of this study were to examine the molecular mechanisms by which EA inhibits pancreatic cancer growth in Balb C nude mice .
3 PANC-1 cells were injected subcutaneously into Balb c nude mice , and tumor-bearing mice were treated with EA .
4 The expression of Akt , Shh and Notch and their target gene products were measured by the immunohistochemistry and Western blot analysis .
5 Treatment of PANC-1 xenografted mice with EA resulted in significant inhibition in tumor growth which was associated with suppression of cell proliferation and caspase-3 activation , and induction of PARP cleavage .
6 EA inhibited the expression of Bcl-2 , cyclin D1 , CDK2 , and CDK6 , and induced the expression of Bax in tumor tissues compared to untreated control group .
7 EA inhibited the markers of angiogenesis ( COX-2 , HIF1alpha , VEGF , VEGFR , IL-6 and IL-8 ) , and metastasis ( MMP-2 and MMP-9 ) in tumor tissues .
8 Furthermore , treatment of mice with EA caused a significant inhibition in phospho-Akt , Gli1 , Gli2 , Notch1 , Notch3 , and Hey1 .
9 EA also reversed epithelial to mesenchymal transition by up-regulating E-cadherin and inhibiting the expression of Snail , MMP-2 and MMP-9 .
10 These data suggest that EA can inhibit pancreatic cancer growth , angiogenesis and metastasis by suppressing Akt , Shh and Notch pathways .
11 In view of the fact that EA could effectively inhibit human pancreatic cancer growth by suppressing Akt , Shh and Notch pathways , our findings suggest that the use of EA would be beneficial for the management of pancreatic cancer .



PMID: 23637631
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types .
1 Gene fusions , like BCR/ABL1 in chronic myelogenous leukemia , have long been recognized in hematologic and mesenchymal malignancies .
2 The recent finding of gene fusions in prostate and lung cancers has motivated the search for pathogenic gene fusions in other malignancies .
3 Here , we developed a "breakpoint analysis" pipeline to discover candidate gene fusions by tell-tale transcript level or genomic DNA copy number transitions occurring within genes .
4 Mining data from 974 diverse cancer samples , we identified 198 candidate fusions involving annotated cancer genes .
5 From these , we validated and further characterized novel gene fusions involving ROS1 tyrosine kinase in angiosarcoma ( CEP85L/ROS1 ) , SLC1A2 glutamate transporter in colon cancer ( APIP/SLC1A2 ) , RAF1 kinase in pancreatic cancer ( ATG7/RAF1 ) and anaplastic astrocytoma ( BCL6/RAF1 ) , EWSR1 in melanoma ( EWSR1/CREM ) , CDK6 kinase in T - cell acute lymphoblastic leukemia ( FAM133B/CDK6 ) , and CLTC in breast cancer ( CLTC/VMP1 ) .
6 Notably , while these fusions involved known cancer genes , all occurred with novel fusion partners and in previously unreported cancer types .
7 Moreover , several constituted druggable targets ( including kinases ) , with therapeutic implications for their respective malignancies .
8 Lastly , breakpoint analysis identified new cell line models for known rearrangements , including EGFRvIII and FIP1L1/PDGFRA .
9 Taken together , we provide a robust approach for gene fusion discovery , and our results highlight a more widespread role of fusion genes in cancer pathogenesis .



PMID: 22952775
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Pristimerin causes G1 arrest , induces apoptosis , and enhances the chemosensitivity to gemcitabine in pancreatic cancer cells .
1 Despite rapid advances in chemotherapy and surgical resection strategies , pancreatic cancer remains the fourth leading cause of cancer related deaths in the United States with a 5-year survival rate of less than 5% .
2 Therefore , novel therapeutic agents for the prevention and treatment of pancreatic cancer are urgently needed .
3 The aim of this study was to investigate the effect of pristimerin , a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae , on inhibition of cell proliferation and induction of apoptosis in three pancreatic cancer cells , BxPC-3 , PANC-1 and AsPC-1 , in both monotherapy and in combination with gemcitabine .
4 Treatment with pristimerin decreased the cell proliferation of all three pancreatic cancer cells in a dose - and time -dependent manner .
5   Treatment of pancreatic cancer cells with pristimerin also resulted in G1-phase arrest which was strongly associated with a marked decrease in the level of cyclins ( D1 and E ) and cyclin -dependent kinases ( cdk2 , cdk4 and cdk6 ) with concomitant induction of WAF1/p21 and KIP1/p27 .
6 Pristimerin treatment also resulted in apoptotic cell death , cleavage of caspase-3 , modulation in the expressions of Bcl-2 family proteins , inhibition of the translocation and DNA -binding activity of NF-kappaB .
7 In addition , pristimerin potentiated the growth inhibition and apoptosis inducing effects of gemcitabine in all three pancreatic cancer cells , atleast in part , by inhibiting constitutive as well as gemcitabine-induced activation of NF-kappaB in both its DNA -binding activity and transcriptional activity .
8 Taken together , these data provide the first evidence that pristimerin has strong potential for development as a novel agent against pancreatic cancer .



PMID: 22869556
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Her2-neu : a target in lung cancer .
1 Aberrant activation of Cyclin D-Cdk4/6 signaling pathway is commonly found in pancreatic ductal adenocarcinoma ( PDAC ) .
2 Here , we show that PD-0332991 , a highly specific inhibitor for Cdk4 and Cdk6 , exerted growth inhibitory effects on three human PDAC cell lines .
3 Microarray analysis revealed that PD-0332991 downregulated cell-cycle-related genes , but upregulated genes implicated in extracellular matrix ( ECM ) remodeling and pancreatic cancer cell invasion and metastasis .
4 Moreover , PD-0332991 enhanced invasion in TGF-beta-responsive PDAC cell lines that harbor a wild-type SMAD4 gene ( COLO-357 , PANC-1 ) , but not in TGF-beta-resistant AsPC-1 cells that harbor a mutated SMAD4 .
5 PD-0332991 also induced epithelial-mesenchymal transition ( EMT ) in COLO-357 and PANC-1 , but not in AsPC-1 cells .
6 Inhibition of CDK4/6 using shRNA mimicked the effects of PD-0332991 on EMT induction .
7 Furthermore , PD-0332991 increased Smad transcriptional activity in luciferase readout assays and activated TGF-beta signaling .
8 SB-505124 , an inhibitor of the type-I TGF-beta receptor ( TbetaRI ) kinase , completely blocked EMT induction by PD-0332991 .
9 When combined with PD-0332991 , SB-505124 inhibited the growth of COLO-357 and PANC-1 cells .
10 Taken together , these data suggest that anti-Cdk4/6 therapy could induce EMT and enhance pancreatic cancer cell invasion by activating Smad -dependent TGF-beta signaling , and that combining PD-0332991 and SB-505124 may represent a novel therapeutic strategy in PDAC .



PMID: 22761470
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Distinguishing gastrointestinal stromal tumors from their mimics : an update .
1 A recurrent gene fusion between EML4 and ALK in 6.7% of non-small cell lung cancers ( NSCLCs ) and NKX2-1 ( TTF1 , TITF1 ) high-level amplifications in 12% of adenocarcinomas of the lung were independently reported recently .
2 Because the EML4-ALK fusion was only shown by a reverse transcription-polymerase chain reaction approach , we developed fluorescent in situ hybridization assays to interrogate more than 600 NSCLCs using break-apart probes for EML4 and ALK .
3 We found that EML4-ALK fusions occur in less than 3% of NSCLC samples and that EML4 and/or ALK amplifications also occur .
4 Μ We also observed that , in most cases in which an EML4/ALK alteration is detected , not all of the tumor cells harbor the lesion .
5 By using a detailed multi-fluorescent in situ hybridization probe assay and reverse transcription-polymerase chain reaction , we have evidence that other , more common mechanisms besides gene inversion exist including the possibility of other fusion partners for ALK and EML4 .
6 Μ Furthermore , we confirmed the NKX2-1 high-level amplification in a significant subset of NSCLC and found this amplification to be mutually exclusive to ALK and EML4 rearrangements .



PMID: 22190866
(Cell)  
Terms: , mouse
Sent# Symbols Sentence Mnemonics
0 Cyclin D1 inhibits whereas c-Myc enhances the cytotoxicity of cisplatin in mouse pancreatic cancer cells via regulation of several members of the NF-kappaB and Bcl-2 families .
1 BACKGROUND :
2 Cisplatin (CDDP) is a drug used for treatment of many types of malignancy but pancreatic cancer is relatively resistant to it .
3 This study aims to determine whether and how cyclin D1 ( D1 ) and c-Myc influence the response of pancreatic cancer cells to CDDP .
4 MATERIALS AND METHODS :
5 Ela-mycPT mouse pancreatic cancer cells were transfected with D1 or c-myc cDNA and treated with CDDP alone or together with NPCD , an inhibitor of cyclin dependent ckinase ( CDK ) 4 and 6 .
6 Reverse transcription followed by polymerase chain reaction ( RT-PCR ) and western blot assays were used to determine the mRNA and protein levels of interested genes .
7 Cell viability was determined using 3 - ( 4 , 5-Dimethylthiazol-2-yl ) -2 , 5-diphenyltetrazolium bromide (MTT) assay .
8 RESULTS :
9 Treatment of Ela-mycPT1 cells with CDDP caused an increase in c-myc expression but a slightly latent decrease in D1 expression , whereas D1 and c-Myc proteins repressed each other .
10 D1 or c-Myc rendered Ela-mycPT1 cells resistant or sensitive , respectively , to CDDP .
11 D1 induced the expression of several members of the NF-kappaB family , including RelA , RelB , Nfkappab1 and Nfkappab2 .
12 D1 also induced BIRC5 and several pro-survival members of the Bcl-2 gene family , including Bcl-2 , Mcl-1 and Bad while it decreased the level of the pro-apoptotic Noxa .
13 Inhibition of CDK4 or CDK6 kinase activity by NPCD did not affect these effects of D1 .
14 In contrast , c-Myc in Ela-mycPT1 and Ela-mycPT4 cells has the opposite effects to D1 on the expression of most of these apoptosis regulating genes .
15 CONCLUSION :
16 Our results suggest that induction of c-Myc and inhibition of D1 may be mechanisms for CDDP to elicit cytotoxicity .
17 On the other hand , D1 induces whereas c-Myc represses the expression of key NF-kappaB family members to induce and repress , respectively , the expression of BIRC5 and several Bcl-2 family members , in turn inhibiting or enhancing the response to CDDP .



PMID: 21956418
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 miR-191 down-regulation plays a role in thyroid follicular tumors through CDK6 targeting .
1 CONTEXT :
2 Well-differentiated thyroid carcinomas include papillary ( PTC ) and follicular ( FTC ) carcinomas .
3 FTC is usually a more aggressive form of cancer than the more common papillary type .
4 Μ miR-191 expression is frequently altered in several neoplasias , being up-regulated in some cases , such as pancreatic carcinomas , and down-regulated in other carcinomas , such as melanomas .
5 OBJECTIVE :
6 The objective was to evaluate the expression and the role of miR-191 in thyroid carcinogenesis .
7 DESIGN :
8 The expression of miR-191 was analyzed in tissues from patients with follicular adenoma ( n = 24 ) , FTC ( n = 24 ) , PTC ( n = 15 ) , anaplastic thyroid carcinoma ( n = 8 ) , and the follicular variant of PTC ( n = 6 ) compared with normal thyroid tissues by quantitative RT-PCR .
9 miR-191 expression was restored in the follicular thyroid cell line WRO , and the effects on cell proliferation , migration , and target expression were evaluated .
10 RESULTS :
11 miR-191 is down-regulated in follicular adenoma , FTC , and follicular variant of PTC .
12 We identified CDK6 , a serine-threonine kinase involved in the control of cell cycle progression , as a novel target of miR-191 .
13 Restoration of miR-191 expression in WRO cells reduces cell growth and migration rate on vitronectin .
14 CDK6 overexpression , correlated with miR-191 down-regulation , was found in follicular adenoma and FTC , suggesting a role of miR-191 down-regulation in the generation of these neoplasias .
15 CONCLUSIONS :
16 Our results suggest that miR-191 down-regulation plays a role in thyroid neoplasias of the follicular histotype , likely by targeting CDK6 .



PMID: 21909380
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Clinical significance of epidermal growth factor receptors in non-small cell lung cancer and a prognostic role for HER2 gene copy number in female patients .
1 BACKGROUND :
2 MicroRNA-34a ( miR-34a ) is a transcriptional target of p53 and is down-regulated in pancreatic cancer .
3 This study aimed to investigate the functional significance of miR-34a in pancreatic cancer progression through its epigenetic restoration with chromatin modulators , demethylating agent 5-Aza-2'-deoxycytidine ( 5-Aza-dC ) and HDAC inhibitor Vorinostat (SAHA) .
4 METHODOLOGY/PRINCIPAL FINDINGS :
5 Re-expression of miR-34a in human pancreatic cancer stem cells ( CSCs ) and in human pancreatic cancer cell lines upon treatment with 5-Aza-dC and SAHA strongly inhibited the cell proliferation , cell cycle progression , self-renewal , epithelial to mesenchymal transition ( EMT ) and invasion .
6 In pancreatic CSCs , modulation of miR-34a induced apoptosis by activating caspase-3/7 .
7 Treatment of pancreatic CSCs with the chromatin-modulating agents resulted in the inhibition of Bcl-2 , CDK6 and SIRT1 , which are the putative targets of miR-34a .
8 MiR-34a upregulation by these agents also induced acetylated p53 , p21 ( WAF1 ) , p27 ( KIP1 ) and PUMA in pancreatic CSCs .
9 Inhibition of miR-34a by antagomiR abrogates the effects of 5-Aza-dC and SAHA , suggesting that 5-Aza-dC and SAHA regulate stem cell characteristics through miR-34a .
10 In CSCs , SAHA inhibited Notch pathway , suggesting its suppression may contribute to inhibition of the self-renewal capacity and induction of apoptosis .
11 Interestingly , treatment of pancreatic CSCs with SAHA resulted in the inhibition of EMT with the transcriptional up-regulation of E-Cadherin and down-regulation of N-Cadherin .
12 Expression of EMT inducers ( Zeb-1 , Snail and Slug ) was inhibited in CSCs upon treatment with SAHA. 5-Aza-dC and SAHA also retard in vitro migration and invasion of CSCs .
13 CONCLUSIONS :
14 The present study thus demonstrates the role of miR-34a as a critical regulator of pancreatic cancer progression by the regulating CSC characteristics .
15   The restoration of its expression by 5-Aza-dC and SAHA in CSCs will not only provide mechanistic insight and therapeutic targets for pancreatic cancer but also promising reagents to boost patient response to existing chemotherapies or as a standalone cancer drug by eliminating the CSC characteristics .



PMID: 21292437
(None)  
Terms: in vitro, xenograft, in vivo, mice
Sent# Symbols Sentence Mnemonics
0 Promoted cancer growth by stimulating cell proliferation and decreasing apoptosis using a lentivirus-based EphB2 RNAi in pancreatic carcinoma CFPAC-1 cells .
1 Several studies have reported the change of EphB2 in a variety of carcinomas and suggested a functional relation between EphB2 and tumor progression .
2 However , its role in human pancreatic carcinoma has not been described .
3 The aim of this study was to evaluate the significance of EphB2 in human pancreatic carcinoma CFPAC-1 cells .
4 A lentivirus-based RNA interference ( RNAi ) vector was designed , synthesized and transfected into CFPAC-1 cells to inhibit EphB2 expression .
5 WST-8 based Colorimetric Assay Cell Counting kit 8 ( CCK-8 ) in vitro and xenograft transplantation model in nude mice was used to evaluate cell proliferation and growth respectively .
6 Cell -cycle and apoptosis were analyzed by flow cytometry ( FCM ) .
7 RT-PCR and Western blot were used to assess mRNA expression and protein levels .
8 EphB2 expression was significantly suppressed both in mRNA and protein levels using the lentivirus-based EphB2 RNAi in CFPAC-1 cells ( P<001 , P<001 ) .
9 Silencing EphB2 stimulated cell growth in vitro ( P<005 ) and proliferation in vivo ( P<001 ) versus Control RNAi .
10 EphB2 RNAi significantly increased S phase cells from 18.15 to 27.18% ( P<005 ) , and significantly decreased G1 phase cells from 72.93 to 57.61% compared with Control RNAi ( P<005 ) .
11 In addition , decreased apoptosis was observed in CFPAC-1 EphB2 RNAi cells compared with Control RNAi cells ( P<001 ) .
12 The apoptosis rate was 1.63% and 7.44% , respectively .
13 Silencing EphB2 increased CyclinD1 , cyclindependent kinase 6 ( CDK6 ) and Bcl-2 expression in both mRNA and protein levels compared with Control RNAi .
14 A lentivirus-based EphB2 RNAi efficiently inhibited EphB2 gene and its protein expression .
15 Silencing EphB2 stimulated pancreatic carcinoma growth by increasing cell proliferation through G1/S phase breakthrough , which relied on a CyclinD1/CDK6 cell -cycle regulated signal .
16 Similarly , EphB2 inhibition also reduced CFPAC-1 cells apoptosis by up-regulating Bcl-2 expression .
17 Thus , atleast in the context of pancreatic carcinoma CFPAC-1 cells , EphB2 plays a tumor suppressor role in cell proliferation and apoptosis .



PMID: 20669973
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 MEK inhibition potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells .
1 The Ras/Raf/MEK/ERK signaling has been implicated in uncontrolled cell proliferation and tumor progression in pancreatic cancer .
2 The purpose of this study is to evaluate the antitumor activity of MEK inhibitor U0126 in combination with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin ( 17-AAG ) in pancreatic cancer cells .
3 Western blotting showed that 17-AAG caused a 2 - to 3-fold transient activation of MEK/ERK signaling in pancreatic cancer cells .
4 The activation sustained for 6 h before phospho-ERK ( p-ERK ) destabilization .
5 The selective MEK inhibitor U0126 completely abolished 17-AAG induced ERK1/2 activation and resulted in more than 80% of phospho-ERK degradation after only 15 min treatment .
6 Moreover , U0126 had complementary effect on 17-AAG regulated oncogenic and cell cycle related proteins .
7 Although 17-AAG downregulated cyclin D1 , cyclin E , CDK4 and CDK6 , it led to cyclin A and CDK2 accumulation , which was reversed by the addition of U0126 .
8 Antiproliferation assay showed that combination of U0126 and 17-AAG resulted in synergistic cytotoxic effect .
9 More importantly , 17-AAG alone only exhibited moderate inhibition of cell migration in vitro , while addition of U0126 dramatically enhanced the inhibitory effect by 2 - to 5-fold .
10 Taken together , these data demonstrate that MEK inhibitor U0126 potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells .
11 The combination of Hsp90 and MEK inhibition could provide a promising avenue for the treatment of pancreatic cancer .



PMID: 20150619
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clear cell carcinoma of the pancreas : an adenocarcinoma with unusual phenotype of duct cell origin .
1 Survival of patients with pancreatic cancer remains poor due to inadequate chemotherapeutic options .
2 Sansalvamide A , a cyclic depsipeptide produced by a marine fungus , has demonstrated significant anticancer activity .
3 We previously observed antiproliferative effects in a series of sansalvamide A analogs in pancreatic cancer cells , one of which was further evaluated in this study .
4 Two human pancreatic cancer cell lines ( AsPC-1 and CD18 ) were incubated with increasing concentrations ( 10-50 muM ) of the sansalvamide analog .
5 Cell proliferation was then measured by thymidine incorporation and cell counting , and cell cycle analysis was determined by flow cytometry .
6 Western blot analysis was used to evaluate expression of cyclin D1 , cdk4 , cdk6 , cyclin E , cyclin A , cdk2 , and p21 .
7 Sansalvamide caused G(1) phase cell cycle arrest in both cell lines , and Western blot analyses demonstrated up-regulation of p21 , down-regulation of cyclins D1 , E , and A , and cdk4 , consistent with G(0)/G(1) cell cycle arrest .
8   Cumulatively the results show that Sansalvamide A attenuates pancreatic cancer cell growth and represents a potential anticancer therapy .



PMID: 19672266
(Cell)  
Terms: in vivo, In vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 Tumour growth and resistance to gemcitabine of pancreatic cancer cells are decreased by AP-2alpha overexpression .
1 BACKGROUND :
2 Activator protein-2alpha ( AP-2alpha ) is a transcription factor that belongs to the family of AP-2 proteins that have essential roles in tumorigenesis .
3 Indeed , AP-2alpha is considered as a tumour-suppressor gene in different tissues such as colonic , prostatic or breast epithelial cells .
4 Moreover , AP-2alpha also participates in the control of colon and breast cancer cells sensitivity towards chemotherapeutic drugs .
5 Despite its potential interest , very few data are available regarding the roles of AP-2alpha in pancreatic cancer .
6 METHODS :
7 We have developed a stable pancreatic CAPAN-1 cell line overexpressing AP-2alpha .
8 Consequences of overexpression were studied in terms of in vivo cell growth , gene expression , migration capacity and chemosensitivity .
9 RESULTS :
10 In vivo tumour growth of CAPAN-1 cells overexpressing AP-2alpha was significantly decreased by comparison to control cells .
11 An altered expression pattern of cell cycle-controlling factors ( CDK-4 , CDK-6 , cyclin-G1 , p27 ( kip1 ) and p57 ( kip2 ) ) was observed in AP-2alpha-overexpressing clones by microarrays and western blot analysis .
12 Promoter activity and ChIP analysis indicated that AP-2alpha induces p27 ( kip1 ) protein levels by direct binding to and transactivation of its promoter .
13 Moreover , AP-2alpha overexpression increased the chemosensitivity of CAPAN-1 cells to low doses of gemcitabine and reduced their in vitro migration capacity .
14 CONCLUSION :
15 Our data suggested that AP-2alpha overexpression could be exploited to decrease in vivo tumour growth of pancreatic cancer cells and to increase their sensitivity to gemcitabine .



PMID: 19407485
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Gene therapy for pancreatic and biliary malignancies .
1 Aberrant expression of microRNAs ( miRNAs ) has emerged as an important hallmark of cancer .
2 However , the putative mechanisms regulating miRNAs per se are only partially known .
3 It is well established that many tumor suppressor genes in human cancers are silenced by chromatin alterations , including promoter methylation and histone deacetylation .
4 We postulated that miRNAs undergo similar epigenetic inactivation in pancreatic cancer .
5 Two human pancreatic cancer cell lines - MiaPACA-2 and PANC-1 - were treated with the demethylating agent , 5-aza-2'-deoxycytidine ( 5-Aza-dC ) or the histone deacetylase inhibitor , trichostatin A , as well as the combination of the two .
6 Expression of miRNAs in control and treated cell lines was assessed using a custom microarray platform .
7 Fourteen miRNAs were upregulated two-fold or greater in each of the cell lines following exposure to both chromatin-modifying agents , including 5 that were in common ( miR-107 , miR-103 , miR-29a , miR-29b , and miR-320 ) to both MiaPACA-2 and PANC-1 .
8 The differential overexpression of miR-107 in the treated cancer cell lines was confirmed by Northern blot assays .
9 Methylation-specific PCR assays for assessment of CpG island methylation status in the 5' promoter region of the miR-107 primary transcript demonstrated complete loss of methylation upon exposure to 5-Aza-dC .
10 Enforced expression of miR-107 in MiaPACA-2 and PANC-1 cells downregulated in vitro growth , and this was associated with repression of the putative miR-107 target , cyclin -dependent kinase 6 , thereby providing a functional basis for the epigenetic inactivation of this miRNA in pancreatic cancer .



PMID: 18541361
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Phorbol 12-myristate 13-acetate inhibits FRO anaplastic human thyroid cancer cell proliferation by inducing cell cycle arrest in G1/S phase : evidence for an effect mediated by PKCdelta .
1 Phorbol 12-myristate 13-acetate ( PMA ) is known to affect a variety of cellular processes , including cell proliferation , differentiation , and migration .
2 PMA has been shown to promote antiproliferative and antimigratory effects in many types of cancer cells .
3 Our findings show that PMA induced a strong antiproliferative effect in two anaplastic ( FRO and ARO ) and one follicular ( ML-1 ) thyroid cancer cell lines , and increased the fraction of FRO cells in G1 phase of the cell cycle .
4 The fractions in the S and G2 phases were decreased .
5 Moreover , PMA evoked a significant increase in the levels of the cell cycle regulators p21Waf1/Cip1 and p27Kip1 .
6 The levels of cyclin D3 and the cyclin -dependent kinases cdk4 and cdk6 decreased , as did the phosphorylation of the Rb - protein .
7 PMA did not induce apoptosis .
8 PMA stimulated the translocation of protein kinase C ( PKC ) alpha , betaI and delta isoforms to the cell membrane .
9 PKCdelta small interfering RNA attenuated the PMA -induced antiproliferative effect and prevented the upregulation of p21Waf1/Cip1 and p27Kip1 .
10 Prolonged stimulation with PMA decreased the phosphorylation of mitogen -activated protein ( MAP ) kinase .
11 PMA also decreased the phosphorylation of Akt and evoked a biphasic change in the phosphorylation of the forkhead box class-O protein (FOXO) : an increase in phosphorylation , followed by a dephosphorylation .
12 In addition , PMA inhibited FRO , ARO and ML-1 cell migration toward serum .
13 The inactive phorbol ester analog 4alpha-phorbol and the diacylglycerol analog 1,2-dioctanoyl-sn-glycerol were without an effect on proliferation and migration .
14 The results indicate that PMA is an effective inhibitor of thyroid cancer cell proliferation and migration by a mechanism involving PKC-MAP kinase/Akt and FOXO signaling .



PMID: 17569628
(Cell)  
Terms: , mice
Sent# Symbols Sentence Mnemonics
0 Epigallocatechin-3-gallate inhibits cell cycle and induces apoptosis in pancreatic cancer .
1 Epidemiological data suggest that epigallocatechin-3-gallate ( EGCG ) possesses chemopreventive properties against cancer .
2 In this study , we examined the molecular mechanisms of EGCG in human pancreatic cancer cells .
3 EGCG caused growth arrest at G1 stage/NN of cell cycle through regulation of cyclin D1 , cdk4 , cdk6 , p21/WAF1/CIP1 and p27/KIP1 , and induced apoptosis through generation of reactive oxygen species and activation of caspase-3 and caspase-9 .
4 EGCG inhibited expressions of Bcl-2 and Bcl-XL and induced expressions of Bax , Bak , Bcl-XS and PUMA .
5 Mouse embryonic fibroblasts ( MEFs ) derived from Bax and Bak double knockout mice exhibited greater protection against EGCG -induced apoptosis than wild-type or single knockout MEFs .
6 EGCG caused Bax activation in p53 -/- MEFs , suggesting that EGCG can induce apoptosis in the absence of p53 .
7 Furthermore , the activities of Ras , Raf-1 and ERK1/2 were inhibited , whereas the activities of MEKK1 , JNK1/2 and p38 MAP kinases were induced by EGCG .
8 Inhibition of cRaf-1 or ERK enhanced EGCG -induced apoptosis , whereas inhibition of JNK or p38 MAP kinase inhibited EGCG -induced apoptosis .
9 EGCG inhibited the activation of p90 ribosomal protein S6 kinase , and induced the activation of cJUN .
10 Our results suggest that EGCG induces growth arrest and apoptosis through multiple mechanisms , and can be used for pancreatic cancer prevention .



PMID: 16547620
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis .
1 BACKGROUND :
2 Approximately 30% of patients with thyroid nodules have indeterminate or suspicious fine-needle aspiration ( FNA ) biopsy results .
3 Because their risk of cancer is approximately 20% , these patients undergo thyroidectomy .
4 We hypothesized that genes that regulate cell -cycle progression would be differentially expressed in malignant versus benign thyroid nodules and could serve as diagnostic markers and markers of disease aggressiveness .
5 METHODS :
6 We used a cDNA array with 96 cell -cycle regulatory genes to identify differentially expressed genes in pooled benign versus malignant thyroid neoplasms .
7 Genes up - or down-regulated by more than 2-fold in malignant thyroid neoplasms were further evaluated by real-time quantitative polymerase chain reaction ( PCR ) in 95 patients with hyperplastic nodules ( n = 19 ) , follicular adenoma ( n = 19 ) , follicular thyroid cancer ( n = 19 ) , the follicular variant of papillary thyroid cancer ( n = 19 ) , and papillary thyroid cancer ( n = 19 ) .
8 RESULTS :
9 cDNA array analysis showed that cyclin B1 , MCM5 , MCM7 , RAD9 , ubiquitin C , CDK6 , SKP2 , and APAF1 were up-regulated in malignant thyroid neoplasms .
10 ✓ Μ Real-time quantitative PCR showed that MCM5 , MCM7 , and RAD9 mRNA expression were significantly higher in malignant than in benign thyroid neoplasms ( RO-ASS-GE
11 ✓ The combined use of MCM5 , MCM7 , and RAD9 mRNA expression had a sensitivity of 98.2% and a specificity of 65.7% . GE-ASS-SR
12 The level of MCM7 mRNA expression was higher in T4 than in T1 , T2 , and T3 differentiated thyroid cancers ( P <00127 ) .
13 CONCLUSIONS :
14 MCM5 , MCM7 , and RAD9 are overexpressed in malignant thyroid neoplasms of follicular cell origin .
15 These genes may be useful markers of malignant thyroid neoplasms as an adjunct to FNA biopsy .
16 MCM7 mRNA expression is higher in locally invasive differentiated thyroid cancer .



PMID: 15841692
(Patient)  
Terms: in vitro, mouse, mouse xenotransplantation models, mice
Sent# Symbols Sentence Mnemonics
0 Cyclin-dependent kinase ( cdk6 ) and p16 in pancreatic endocrine neoplasms .
1 Activation of the N-ras gene by point mutation occurs in about 15% of all human melanomas .
2 Μ In recently established severe combined immunodeficiency ( SCID ) mouse xenotransplantation models for human melanoma , we demonstrated that mutated N-ras not only contributes to tumour growth by enhancing cellular proliferation , but also by blocking apoptosis .
3 Mutated N-ras overexpression protected human melanomas from naturally occurring apoptosis and , in a more pronounced way , from chemotherapy-induced apoptosis in vitro and in vivo .
4 Given the potential clinical importance of these findings we sought to determine the underlying mechanism .
5 Μ We found that mutated N-ras specifically upregulates the expression of the anti-apoptosis gene bcl-2 in two human melanoma cell lines in vitro and in SCID mice .
6 Neither the expression of the anti-apoptotic protein Bcl-xL nor that of the pro-apoptotic proteins Bax and Bak were altered in cells expressing mutated N-Ras .
7 The increase in Bcl-2 expression mediated by mutated ras therefore qualifies as a rational explanation for the enhanced chemoresistance of human melanoma expressing mutated N-Ras .



PMID: 14976133
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Suppression of human pancreatic cancer cell proliferation by AGN194204 , an RXR-selective retinoid .
1 Retinoids may be useful agents for the treatment of pancreatic cancer .
2 However , retinoic acid receptor ( RAR )- selective retinoids produce unwanted side effects .
3 In contrast , retinoid X receptor ( RXR )- selective retinoids produce fewer side effects ; however , it was not known whether RXR-selective retinoids could reduce pancreatic tumor cell proliferation .
4 In the present study , the novel RXR-selective retinoid , AGN194204 , was compared with that of other retinoids for the ability to suppress pancreatic cancer cell proliferation .
5 We treated various pancreatic cancer cell lines with receptor -selective ligands and cytotoxic agents and monitored the effects on cell proliferation , markers of apoptosis and cell cycle .
6 Our results indicate that AGN194204 , at concentrations >10 nM , inhibits proliferation of MIA PaCa-2 and BxPC-3 cells but not the proliferation of AsPC-1 cells .
7 Moreover , in BxPC-3 and MIA PaCa-2 cells , AGN194204 was 10-100 times more effective than RAR-selective retinoids .
8 AGN194204 -dependent suppression of MIA PaCa-2 cell proliferation is associated with reduced cyclin E and cyclin-dependent kinase 6 ( cdk6 ) level , but cyclin D1 , cdk2 and cdk4 content is not altered .
9 In addition , p27 level increases 2-fold .
10 The RXR-selective antagonist , AGN195393 , reverses the AGN194204 -dependent growth inhibition and the decline in cyclin E and cdk6 levels .
11 In contrast , these changes are not reversed by treatment with the RAR antagonist , AGN193109 .
12 AGN194204 did not appear to alter cell apoptosis as measured by change in cleavage of procaspase-3 , -8 or -9 .
13 We also examined the effects AGN194204 co-treatment with cytotoxic agents .
14 Treatment of MIA PaCa-2 cells with AGN194204 + cisplatin , gemcitabine , 5-fluorouracil , interferon ( IFN ) alpha or IFNgamma resulted in an additive but not synergistic reduction in MIA PaCa-2 cell number .
15 These results indicate that AGN194204 , an RXR-selective retinoid , is a more effective inhibitor of pancreatic cell proliferation than the RAR-selective retinoids , and further indicate that AGN194204 produces an additive reduction in cell number when given with other agents .
16 Our results suggest that RXR-selective ligands , which are less toxic than RAR-selective ligands , may be suitable agents for the treatment of pancreatic cancer .



PMID: 14669326
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Oil A induces apoptosis of pancreatic cancer cells via caspase activation , redistribution of cell cycle and GADD expression .
1 AIM :
2 To explore the mechanisms of effects of oil A on apoptosis of human pancreatic cancer cells .
3 METHODS :
4 Cellular DNA content was analyzed by flow cytometry .
5 Western blotting was used for caspase-3 and PARP , caspase-7 , caspase-9 , cytochrome c , Bcl-2 , Bax , Mcl-1 , cyclinA , cyclin B1 , cyclin D1 , cyclin E , CDK2 , CDK4 , CDK6 , P21 , P27 , GADD45 , GADD153 .
6 RESULTS :
7 The caspase-3 , caspase-7 , and caspase-9 activities were significantly increased as well as the cleavage of caspase-3 , downstream substrate poly-ADP ribose polymerase ( PARP ) was induced .
8 The amount of cytochrome c in the cytosolic fraction was increased , while the amount of cytochrome c in the mitochondrial fraction was decreased after oil A treatment .
9 The anti-apoptosis proteins Bcl-2 and Mcl-1 were decreased in parallel and Bax increased , indicating that Bcl-2 family proteins-mitochondria-caspase cascade was responsible for oil-induced apoptosis .
10 The proportion of cells in the G0/G1 decreased in MiaPaCa-2 and AsPC-1 cells after the treatment of oil A for 24 hours .
11 The number of cells in S phase was increased in two cancer cell lines at 24 hours .
12 Therefore , cells were significantly accumulated in G2/M phase .
13 The cells with a sub-G0/G1 DNA content , a hallmark of apoptosis , were seen at 24 hours both in MiaPaCa-2 and AsPC-1 cells following exposure to oil A .
14 The expression of cyclin A and cyclin B1 was slightly decreased and cyclin D1 levels were markedly lowered in MiaPaCa-2 cells .
15 The expression of cyclin A and cyclin B1 was markedly decreased and cyclin D1 levels were slightly lowered in AsPC-1 cells , while cyclin E was not affected and the levels of CDK2 , CDK4 , and CDK6 were unchanged in MiaPaCa-2 and AsPC-1 cells .
16 In response to oil A , P21 expression was increased , but P27 expression was not affected .
17   The expression of both GADD45 and GADD153 was increased in two cell lines following oil A treatment .
18 CONCLUSION :
19 Oil A induces apoptosis of pancreatic cancer cells via activating caspase cascade , modifying cell cycle progress and changing cell cycle-regulating proteins and GADD expression .



PMID: 12883267
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Arsenic trioxide induces apoptosis in pancreatic cancer cells via changes in cell cycle , caspase activation , and GADD expression .
1 We have previously shown that arsenic trioxide blocks proliferation and induces apoptosis in human pancreatic cancer cells at low , non-toxic concentrations .
2 The mechanisms of the apoptosis was investigated in MiaPaCa2 and PANC-1 cells that have been previously shown to be responsive to arsenic trioxide .
3 The results show the caspase-3 , caspase-7 , and caspase-9 are all activated by arsenic trioxide , together with cleavage of the downstream caspase-3 target poly ADP ribose polymerase ( PARP ) .
4 Expression of the anti-apoptosis proteins , Bcl-2 and Mcl-1 expression decreased time-dependently while Bax expression increased .
5 These findings indicate that the Bcl family of proteins , the mitochondrial pathway and activation of the caspase cascade are responsible for arsenic-induced apoptosis .
6 Flow cytometric analysis revealed changes of cell cycle distribution from a G0/G1 phase arrest at 24 hours to G2/M phase arrest at 72 hours following arsenic treatment .
7 The sub-G0/G1 cell population of apoptotic cells was increased at these times .
8 Arsenic increased expression of the P21 protein and decreased levels of cyclin A , cyclin B1 and cyclin D1 , but expression of CDK2 , CDK4 , CDK6 , and cyclin E were not affected .
9 Arsenic trioxide markedly enhanced the expression of GADD45 and GADD153 in a time -dependent manner .
10 In summary , arsenic trioxide induced apoptosis in pancreatic cancer cells through activating the caspase cascade via the mitochondrial pathway , GADD expression and by modifying cell cycle progress and changes in several cycle-regulating proteins .
11 This old drug may be valuable for treatment of pancreatic cancer .



PMID: 11687897
(Cell)  
Terms: in vivo, xenograft
Sent# Symbols Sentence Mnemonics
0 Adenovirus-mediated wt-p16 reintroduction induces cell cycle arrest or apoptosis in pancreatic cancer .
1 Pancreatic cancer has long carried poor prognosis .
2 The development of new therapeutic approaches is particularly urgent .
3 Inactivation of the tumor-suppressor gene p16 (INK4a/CDKN2) , a specific inhibitor of the cyclin -dependent kinases CDK4 and CDK6 , is the most common genetic alteration in human pancreatic cancer , making it an ideal target for gene replacement .
4 Here we transfected tumor cells using a recombinant adenovirus containing the wt-p16 cDNA (Ad5RSV-p16) .
5 The overexpression of p16 decreased cell proliferation in all four human pancreatic tumor cell lines ( NP-9 , NP-18 , NP-29 , and NP-31 ) .
6 However , G1 arrest and senescence were observed in only three .
7 In contrast , the fourth ( NP-18 ) showed a significant increase in apoptosis .
8 Μ This differential behavior may be related to the differences found in the expression level of E2F-1 .
9 Experiments on subcutaneous pancreatic xenografts demonstrated the effectiveness of p16 in the inhibition of pancreatic tumor growth in vivo .
10 Taken together , our results indicate that approaches involving p16 replacement are promising in pancreatic cancer treatment .



PMID: 11325039
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The physiology of p16 ( INK4A )- mediated G1 proliferative arrest .
1 Phosphorylation of the product of the retinoblastoma susceptibility gene ( Rb ) physiologically inactivates its growth-suppressive properties .
2 Rb phosphorylation is mediated by cyclin-dependent kinases ( CDKs ) , whose activity is enhanced by cyclins and inhibited by CDK inhibitors .
3 p16 ( INK4A ) is a member of a family of inhibitors specific for CDK4 and CDK6 .
4 p16 ( INK4A ) is deleted and inactivated in a wide variety of human malignancies , including familial melanomas and pancreatic carcinoma syndromes , indicating that it is an authentic human tumor suppressor .
5 Although one mechanism for its tumor suppression may be prevention of Rb phosphorylation , thereby causing G1 arrest , many normal cell types express p16 ( INK4A ) , and are still able to traverse the cell cycle .
6 In a search for other mechanisms , we have found that p16 ( INK4A ) is required for p53 -independent G1 arrest in response to DNA-damaging agents , including topoisomerase I and II inhibitors .
7 Thus , like other tumor suppressors , p16 ( INK4A ) plays an essential role in a DNA-damage checkpoint that leads to cell cycle arrest .



PMID: 11299771
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Apigenin inhibits growth and induces G2/M arrest by modulating cyclin-CDK regulators and ERK MAP kinase activation in breast carcinoma cells .
1 We have previously reported that apigenin inhibits the growth of thyroid cancer cells by attenuating epidermal growth factor receptor ( EGF-R ) tyrosine phosphorylation and phosphorylation of ERK mitogen -activated protein ( MAP ) kinase .
2 In this study , we assessed the growth inhibitory effect of apigenin on MCF-7 breast carcinoma cells that express two key cell cycle regulators , wild-type p53 and the retinoblastoma tumor suppressor protein ( Rb ) , and MDA-MB-468 breast carcinoma cells that are mutant for p53 and Rb negative .
3 We found that apigenin potently inhibited growth of both MCF-7 and MDA-MB-468 breast carcinoma cells .
4 The approximate IC50 values determined after 3 days incubation , were 7.8 micrograms/ml for MCF-7 cells , and 8.9 micrograms/ml for MDA-MB-468 cells , respectively .
5 Because the cell cycle studies using FACS showed that both MCF-7 and MDA-MB-468 cells were arrested in G2/M phase after apigenin treatment , we studied the effects of apigenin on cell cycle regulatory molecules .
6 We observed that G2/M arrest by apigenin involved a significant decrease in cyclin B1 and CDK1 protein levels , resulting in a marked inhibition of CDK1 kinase activity .
7 Apigenin reduced the protein levels of CDK4 , cyclins D1 and A , but did not affect cyclin E , CDK2 and CDK6 protein expression .
8 In MCF-7 cells , apigenin markedly reduced Rb phosphorylation after 12 h .
9 We also found that apigenin treatment resulted in a dose - and time -dependent inhibition of ERK MAP kinase phosphorylation and activation in MDA-MB-468 cells .
10 These results suggest that apigenin is a promising antibreast cancer agent and its growth inhibitory effects are mediated by targeting different signal transduction pathways in MCF-7 and MDA-MB-468 breast carcinoma cells .



PMID: 10922411
(Patient)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families .
1 BACKGROUND :
2 : Inherited mutations in the CDKN2A tumor suppressor gene , which encodes the p16 ( INK4a ) protein , and in the cyclin-dependent kinase 4 ( CDK4 ) gene confer susceptibility to cutaneous malignant melanoma .
3 We analyzed families with two or more cases of melanoma for germline mutations in CDKN2A and CDK4 to elucidate the contribution of these gene defects to familial malignant melanoma and to the occurrence of other cancer types .
4 METHODS :
5 Μ : The entire CDKN2A coding region and exon 2 of the CDK4 gene of an affected member of each of 52 families from southern Sweden with atleast two cases of melanoma in first - or second-degree relatives were screened for mutations by use of polymerase chain reaction-single - strand conformation polymorphism analysis .
6 Statistical tests were two-sided .
7 RESULTS :
8 Μ : CDKN2A mutations were found in 10 ( 19% ) of the 52 families .
9 Nine families carried an identical alteration consisting of the insertion of arginine at position 113 of p16 ( INK4a ) , and one carried a missense mutation , in which the valine at position 115 was replaced with a glycine .
10 The 113insArg mutant p16 (INK4a) was unable to bind cdk4 and cdk6 in an in vitro binding assay .
11 Six of the 113insArg families had atleast one member with multiple primary melanomas ; the 113insArg families also had a high frequency of other malignancies-in particular , breast cancer ( a total of eight cases compared with the expected 21 ; P =0014 ) and pancreatic cancer ( a total of six cases compared with the expected 016 ; P<0001 ) .
12 Families with breast cancer also had a propensity for multiple melanomas in females , suggesting that a sex -dependent factor may modify the phenotypic expression of CDKN2A alterations .
13 CONCLUSIONS :
14 : Our findings confirm that the majority of CDKN2A-associated melanoma families in Sweden are due to a single founder mutation .
15 They also show that families with the CDKN2A 113insArg mutation have an increased risk not only of multiple melanomas and pancreatic carcinoma but also of breast cancer .



PMID: 9827724
(Patient)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Genetic and epigenetic alterations of the cyclin -dependent kinase inhibitors p15INK4b and p16INK4a in human thyroid carcinoma cell lines and primary thyroid carcinomas .
1 BACKGROUND :
2 D-type cyclins , in association with the cyclin -dependent kinases CDK4 and CDK6 , promote progression through the G1 phase of the cell cycle .
3 CDK activity is modulated by inhibitors such as p15INK4b and p16INK4a .
4 Loss of function of p15INK4b and p16INK4a ( multiple tumor suppressor-I and CDK4 inhibitor ) determines impairment in the control of the cell cycle and contributes to the transformation of several cell types .
5 METHODS :
6 The authors examined 20 thyroid neoplasms ( 12 papillary carcinomas and 8 follicular adenomas ) and 4 human thyroid carcinoma cell lines for gene mutations and epigenetic modifications of the p15INK4b and p16INK4a genes by Southern blot analysis , single strand conformation polymorphism , and a polymerase chain reaction-based methylation assay .
7 RESULTS :
8 Abnormalities of p16 were found in the four cell lines studied .
9 In follicular carcinoma ( WRO ) cells , both the p15 and p16 genes were homozygously deleted .
10 Μ Undifferentiated carcinoma ( FRO ) cells had a nonsense point mutation at codon 72 ( CGA-TGA , Arg-Stop ) of p16 , whereas the poorly differentiated papillary carcinoma ( NPA ) line harbored a point mutation at the exon 1-intron 1 boundary that altered the donor splicing site and caused an aberrantly spliced form of p16INK4a .
11 Furthermore , p16 allelic loss was evident in the DNA of both FRO and NPA cells .
12 Finally , p16 expression was absent in the ARO cell line , likely due to a de novo methylation of exon 1 of p16INK4a .
13 Μ Regarding the primary thyroid tumors , a missense point mutation at codon 91 was found in 1 of 12 papillary thyroid carcinomas ( GCC-GTC , Ala-Val ) .
14 Μ No mutations were found in follicular adenomas .
15 However , in 6 of 20 primary tumors there was hypermethylation at exon 1 of p16 .
16 CONCLUSIONS :
17 Μ The high prevalence of p15 and p16 mutations in the cell lines described suggests involvement of these genes in immortalization in vitro .
18 The p16 defects may have preexisted in a small subclone of the primary tumor that were selected for in vitro .
19 Alternatively , p16 mutations may have arisen de novo during cell culture .
20 Mutations of p15INK4b and p16INK4a do not appear to be critical events in the development of follicular adenomas or papillary carcinomas .
21 However , de novo methylation of the 5' CpG island of p16 is common in primary tumors , indicating that the function of this gene may be lost as an epigenetic event during disease progression .



PMID: 7566978
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 p16 proteins from melanoma-prone families are deficient in binding to Cdk4 .
1 The tumor suppressor candidate p16INK4 is a cyclin -dependent kinase inhibitor that inhibits cell proliferation .
2 The p16 coding gene is often mutated in glioblastomas , pancreatic adenocarcinomas and melanoma-prone pedigrees , but , until recently , the significance of these allelic variants has remained unclear .
3 Μ Here , we used interaction mating and coprecipitation to measure interaction of seven p16 allelic variants detected in melanoma-prone pedigrees with Cyclin-dependent kinases ( Cdks ) .
4 Μ We found that most variants were deficient in interaction with Cdk4 and Cdk6 .
5 Μ One defective variant was found both in cancer prone families and in the control population and therefore previously defined as a common polymorphism .
6 Another variant , which is weakly linked to familial cancer , is only slightly affected in interaction with Cdks .
7 These results are consistent with the idea that p16 allelic variants that decrease Cdk interaction predispose individuals who carry them to an increased risk of cancer .
8 Μ Moreover , they suggest that determination of affinity between p16 mutants and partner proteins may help identify functionally-significant allelic variants not detected by classical human genetic techniques .



PMID: AACR_2012-3055
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 PD-0332991 , a selective cyclin -dependent - kinase 4/6 Inhibitor , upregulates multiple genes promoting invasion and metastasis in pancreatic ductal adenocarcinoma .
1 Deregulation of the Cyclin D-CDK4/6-Rb-E2F signaling pathway is among the most commonly found aberrations in human pancreatic ductal adenocarcinoma ( PDAC ) .
2 PD-0332991 is an orally available , highly specific and reversible inhibitor for Cdk4 and Cdk6 , and demonstrates in vitro and in vivo growth inhibitory effects in multiple tumor types .
3 However , the potential usefulness of PD-0332991 in PDAC is currently unknown .
4 In this study , we examined the effects of PD-0332991 on multiple human pancreatic cancer cell lines , and we found that this agent inhibited Rb phosphorylation and E2F target gene expression , and induced G0/G1 cell cycle arrest .
5 However , the growth inhibitory effect was only transient , due to the rapidly emerging compensatory changes of the G1/S machinery components , including upregulation of CyclinD1 , Cdk4 , and Cdk6 , and downregulation of Rb , p107 , and p130 .
6 Microarray analysis revealed that incubation with PD-0332991 upregulated multiple genes which promote pancreatic cancer invasion , metastasis , angiogenesis , and chemoresistance , including LAMC2 , CYR61 , SERPINE1 , F3 , ABCA1 , ASNS , and DUSP1 .
7 In addition , using matrigel-coated transwell invasion chambers , we demonstrated that incubation with PD-0332991 enhanced the invasiveness of human pancreatic cancer cells .
8 These observations suggest that PD-0332991 may have the potential to cause deleterious effects in PDAC by modulating gene expression in a manner that could promote cancer spread , metastasis , and chemoresistance .



PMID: AACR_2016-282
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Pan-RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4 and 6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1 .
1   Dynamics of mutant BRAF V600E in free circulating DNA ( fcDNA ) of non-melanoma cancer patients ( pts ) in response to treatment with BRAF and MEK/EGFR inhibitors. .



PMID: AACR_2012-3697
(Cell)  
Terms: Phase II study, xenograft
Sent# Symbols Sentence Mnemonics
0 Phase II study of therapy selected by molecular profiling in patients with previously treated metastatic pancreatic cancer - SU2C-001 .
1 We have completed a second line Phase II study of therapy to be selected by molecular profiling in 35 patients with previously treated metastatic pancreatic cancer .
2 On this study all patients have a biopsy of a metastatic lesion ( usually liver ) .
3 Therapeutic targets are identified by profiling the metastatic biopsies with the combined use of immunohistochemistry ( IHC ) , comparative genomic hybridization ( CGH ) on sorted tumor populations , and correlating gene expression microarray data to that of a panel of xenografts for which drug sensitivity has been previously determined .
4 The IHC assays are performed in a CLIA certified laboratory and include the following therapeutic targets : MRP1 , TOPO1 , MGMT , PGP , Her2/Neu , PTEN , c-kit , RRM1 , EGFR , BCRP , PDGFR , TOP2A , TS , ERCC1 , SPARC , ER , PR , and AR .
5 In addition each sample is screened by PCR for the presence of the most common K-RAS mutations .
6 Gene expression microarray analysis is performed at John Hopkins University using Affymetrix U133 Plus 2.0 gene arrays .
7 For CGH analysis flow sorted nuclei of diploid and aneuploid tumor cell populations are processed and hybridized to 400,000 feature CGH arrays .
8 Μ We have identified distinct high level focal amplicons targeting AKT2 , LYN , RET , CDK6 , K-RAS , MYCBP , BCL11A , RASA1 and WNT6 , and gene specific homozygous deletions including CDKN2A , PTEN , MAP2K4 , RASA1 and PARK2 in the sorted aneuploid tumor nuclei .
9   In an effort to elucidate new targets and potential contexts of vulnerability based on the results of this trial , we have extracted combined gene level data for each patient and present these mapped to 32 pancreatic specific pathways and processes .



PMID: AACR_2017-2337
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 miR-6883 and family miRNAs induce G1-arrest in colon cancer cells by targeting CDK4/6. .
1 Background : Nilotinib (N) , a selective tyrosine kinase inhibitor ( TKI ) targeting KIT , PDGFRA , and BCR-ABL with activity against imatinib ( IM )- sensitive and -resistant GIST cells , has shown efficacy in phase I and II trials .
2 ENEST g3 , a phase III , randomized , open-label , multicenter trial was performed to test N versus best supportive care ( BSC ) with physician choice to continue or stop IM or sunitinib (S) in patients ( pts ) with advanced/metastatic GIST who had failed IM and S .
3 Methods : Pts were randomized 2 : 1 to N 400 mg bid or to the control arm ( C = BSC , BSC+IM , or BSC+S , at physician discretion ) .
4 Primary endpoint was progression-free survival ( PFS ) per RECIST assessed by blinded central radiology review ( CRR ) .
5 Results : 248 pts were included in the intent-to-treat ( ITT ) population : N = 165 , C = 83 ( BSC = 6 , BSC+IM = 54 , BSC+S = 23 ) .
6 No significant difference in PFS between the N and C arms was observed based on CRR ( p = 05555 ; median PFS = 109 vs. 111 days , respectively ) .
7 There was major discordance in local investigator assessment of PFS in favor of N ; median PFS for N = 119 vs . C = 70 ( p = 00007 ) .
8 Median overall survival ( OS ) was 332 vs. 280 days in the N and C arms , respectively ( p = 029 ; ns ) .
9 51 pts ( 21% ) had >2 prior regimens of which 10 pts entered the study without clear documented progression .
10 Exploratory analyses were done on "true 3rd-line" pts ( n = 197 ) , defined as those who had objectively progressed after IM and S regimens given sequentially only once .
11 A significant difference in median OS was observed : 405 vs. 280 days for N ( n = 132 ) vs . C ( n = 65 ) , respectively ( p = 002 ) .
12 N was well tolerated , with no differences in adverse events between arms .
13 Conclusions : No statistical differences in PFS or OS for N vs . BSC ( usually with continuation of TKI therapy ) were demonstrated in the ITT population .
14 The mixed pt population entering the study ( multiple lines of previous therapy , lack of documented failure to prior therapy ) and investigator choice to include TKI continuation in the BSC control make the outcomes difficult to interpret .
15 Given the almost 2-month improvement in median OS in the ITT population and 4-month improvement in true 3rd - line pts , further study of N activity in well-defined GIST patient populations is warranted .



PMID: AACR_2014-3384
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 An internal ribosomal entry site in the 5-untranslated region of p16INK4a mRNA provides a novel mechanism for the regulation of its translation .
1 In mammalian systems , controlled progression through the cell cycle is essential for normal proliferation and its loss is a hallmark of malignancy .
2 p16INK4a inhibits the cyclin -dependent kinases CDK4 and CDK6 , thereby keeping the retinoblastoma protein ( pRB ) in a hypo-phosphorylated state , which can lead to G1/S checkpoint activation .
3 In addition p16INK4a plays a crucial role in the process of replicative senescence .
4 p16INK4a loss or inactivation is associated with predisposition to melanoma , pancreatic cancer and other malignancies , highlighting its recognized function as a tumor suppressor .
5 Given its critical role in cell homeostasis , there is much interest in understanding the molecular regulators of p16INK4a expression .
6 Here we report that p16 belongs to the expanding group of proteins whose translation is influenced by sequence/structural features of the 5UTR mRNA that are endowed of cellular Internal Ribosome Entry Site ( IRES ) activity .
7 To study the potential for p16INK4a 5UTR to drive cap -independent translation we developed a dual-luciferase assay using a bicistronic vector ( named pRuF ) , where wild type or deletion mutants of the p16INK4a 5UTRs were cloned as intervening sequence between Renilla and Firefly luciferase cDNAs .
8 The p16INK4a 5UTR sequence in inverted orientation was included as additional control .
9 Results of reporters relative activity coupled to control analyses of actual bicistronic mRNA transcription , indicated that the wild type p16INK4a 5UTR could stimulate Firefly luciferase translation .
10 The IRES-like activity could not be mapped to a specific region of the 5UTR based on results with deletion constructs , and was two-fold stronger compared to the cMYC 5UTR , a known cellular IRES used as a control .
11 Notably , hypoxic stress in particular , but also the treatment with mTOR inhibitors , enhanced the translation-stimulating property of the p16INK4a 5UTR .
12 RNA immuno-precipitation ( RIP ) assays performed in the p16-positive melanoma-derived cell line SK-Mel-28 suggest that the RNA -binding protein YBX-1 , known to act in translation control , can participate in p16 INK4a translation .
13 Experiments were YBX-1 was over-expressed or knocked-down by si-RNA confirmed its involvement in p16INK4a cap -independent translational regulation .
14 Taken collectively , our results suggest that the 5UTR region can modulate p16INK4a mRNA translation efficiency .