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

Molecular Cancer

Research

Patrick Breheny¹  Michael R. Miller²  Nadine Bannick²  Michael D. Henry³  Deqin Ma⁴  Eric Askeland⁵  Sarah L. Mott⁶  James Brown⁷  James Schappet⁸ 

[1] Department of Biostatistics, University of Iowa Carver College of Medicine, Iowa, USA;Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, 6-510 Bowen Science Bldg, Iowa, USA;Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, 6-510 Bowen Science Bldg, Iowa, USA;Department of Pathology, University of Iowa Carver College of Medicine, Iowa, USA;Holden Comprehensive Cancer Center, Iowa, USA;Department of Pathology, University of Iowa Carver College of Medicine, Iowa, USA;Department of Urology, University of Iowa Carver College of Medicine, Iowa, USA;Holden Comprehensive Cancer Center, Iowa, USA;Holden Comprehensive Cancer Center, Iowa, USA;Department of Urology, University of Iowa Carver College of Medicine, Iowa, USA;Institute for Clinical and Translational Sciences, Iowa, USA;

关键词: (MESH Terms);    Dystroglycans;    Carcinoma;    Renal cell;    Glycosylation;   

DOI  :  10.1186/s12943-015-0416-z

 received in 2015-03-21, accepted in 2015-07-17,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundDystroglycan (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 αDG, which involves at least 13 distinct genes. Prior work has shown loss of αDG 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.MethodsUsing 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.ResultsAnalysis 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.ConclusionsReduced levels of GYLTL1B and ISPD mRNA associated with increased patient mortality and are the likely cause of αDG hypoglycosylation in ccRCC.

【 授权许可】

Unknown   
© Miller et al. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.