Downregulation of dystroglycan glycosyltransferases LARGE2 and ISPD associate with increased mortality in clear cell renal cell carcinoma

作者：Miller Michael R; Ma Deqin; Schappet James; Breheny Patrick; Mott Sarah L; Bannick Nadine; Askeland Eric; Brown James; Henry Michael D^*

来源：Molecular Cancer, 2015, 14(1): 141.

DOI：10.1186/s12943-015-0416-z

• Dystroglycans
• Carcinoma
• Renal cell
• Glycosylation

Background: Dystroglycan (DG) is a cell-surface laminin receptor that links the cytoskeleton to the extracellular matrix in a variety of epithelial tissues. Its function as a matrix receptor requires extensive glycosylation of its extracellular subunit alpha DG, which involves at least 13 distinct genes. Prior work has shown loss of aDG glycosylation in an assortment of carcinomas, including clear cell renal cell carcinoma (ccRCC) though the cause (s) and functional consequences of this loss are still unclear.
Methods: Using The Cancer Genome Atlas (TCGA) database, we analyzed the DG glycosylation pathway to identify changes in mRNA expression and correlation with clinical outcomes. We validated our findings with a cohort of 65 patients treated with radical nephrectomy by analyzing DG glycosylation via immunohistochemistry and gene expression via qRT-PCR.
Results: Analysis of TCGA database revealed frequent dysregulation of a subset of DG glycosyltransferases. Most notably, there was a frequent, significant downregulation of GYLTL1B (LARGE2) and ISPD. DG glycosylation is frequently impaired in ccRCC patient samples and most strongly associates with downregulation of GYLTL1B.
Conclusions: Reduced levels of GYLTL1B and ISPD mRNA associated with increased patient mortality and are the likely cause of aDG hypoglycosylation in ccRCC.

• 出版日期2015-7-30