PMID: PMC6243375-1-5

 

    Legend: Gene, Sites

Title : Mapping aberrant O‐linked glycoproteome associated with human kidney tumor

Abstract :

1. To identify changes in the O‐linked glycoproteome between normal and tumor kidney tissue, spectral counting label‐free quantification of the EXoO identified peptides was used (Fig 3A)
2. This identified 56 O‐linked gl glycoproteins as exhibiting significant change using scoring criteria of at least a twofold change together with a difference in at least 10 PSMs between normal and tumor samples (Fig 3B and Appendix Table S1)
3. The most striking change observed was the dramatic increase in O‐linked glycans, primarily in the core 1 structure Hex(1)HexNAc(1) across the 163 and 82 sites mapped in VCAN and ACAN , respectively (Fig 3C)
4. For example, 35 PSMs were found at Thr‐2983 of VCAN from tumor tissue but none in normal tissue samples (Fig 3C red asterisk in upper panel)
5. Similarly, 109 PSMs were detected at Thr‐374 of ACAN from tumor tissue and only five in normal tissue (Fig 3C red asterisk in lower panel)
6. Owing to unclear substrate specificity of OpeRATOR for O‐linked glycans, the site‐specific O‐linked glycosylation by glycans in addition to Core 1 glycans merits future investigation
7. VCAN and ACAN are known proteoglycans that have long sugar chains in normal condition (Binder et al, 2017)
8. The extensive addition of short core 1 O‐linked glycans to these two proteins would be expected to enhance their mucin‐type properties such as resistance to enzymatic digestion and improved stiffness, and this in turn may alter their biological and biomechanical properties producing some remodeling of the tumor microenvironment (Kufe, 2009)
9. In addition to VCAN and ACAN , an average of 4.3‐fold increase was detected in 14 sites across fibulin‐2 ( FBLN2 ), a glycoprotein known to be involved in stabilizing the VCAN and ACAN network for growth and metastasis of tumor (Olin et al, 2001; Baird et al, 2013; Fig 3D and Appendix Table S1)
10. Remodeling of the extracellular matrix ( ECM ) in tumor tissue might be further underpinned by the significant changes in other ECM ‐related proteins such as ELN , LTBP1 , LTBP2 , LTBP3 , EMILIN2 , FN1 , CDH16 , and EMCN and collagens COL8A1 , COL12A1 , COL28A1 , and COL26A1 , and enzymes including ITIH2 , MMP14 , ADAMTS7 , SERPINE1 , ANPEP , PAPLN , ADAMTSL5 , GGT5 , and CPXM1 detected in tumor tissue (Fig 3D and Appendix Table S1)
11. This type of fine‐tuning of the ECM network might be critical to supporting tumorigenesis and tumor progression (Lu et al, 2012)
12. In addition, carbonic anhydrase 9 ( CA9 ) and angiopoietin‐related protein 4 ( ANGPTL4 ), proteins known to respond to tumor hypoxia (Sedlakova et al, 2014; Carbone et al, 2018), showed 13‐ and 3.6‐fold increases, respectively, in tumor tissue (Fig 3D and Appendix Table S1)
13. Finally, EGF‐containing fibulin‐like extracellular matrix protein 1 ( EFEMP1 ), which binds to epidermal growth factor receptor ( EGFR ) to promote tumor growth, invasion, and metastasis (Yin et al, 2016), showed a threefold increase across seven O‐linked glycosylation sites in tumor tissue (Fig 3D and Appendix Table S1)
14. By contrast, both IGHA1 and MUC1 , known O‐linked glycoproteins , showed no detectable change between normal and tumor tissue indicating that the changes in O‐linked glycoproteins observed in tumor tissue are highly selective

Output (sent_index, trigger, protein, sugar, site):

• 13. glycosylation, , -, -, sites
• 14. glycoproteins, , glycoproteins, -, -
• 2. glycoproteins, , glycoproteins, -, -
• 9. glycoprotein, , fibulin‐2, -, -
• 9. glycoprotein, , glycoprotein, -, -

Output(Part-Of) (sent_index, protein, site):

• 13. O‐linked, sites
• 4. VCAN, Thr‐2983
• 5. ACAN, Thr‐374

*Output_Site_Fusion* (sent_index, protein, sugar, site):

 

Protein	NCBI ID	SENTENCE INDEX