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

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

doi:10.1186/s12943-015-0416-z

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

Journal article

Open access

Peer reviewed

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

Michael R Miller, Deqin Ma, James Schappet, Patrick Breheny, Sarah L Mott, Nadine Bannick, Eric Askeland, James Brown and Michael D Henry

Molecular cancer, Vol.14(1), pp.141-141

07/30/2015

DOI: 10.1186/s12943-015-0416-z

PMCID: PMC4518861

PMID: 26220087

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Abstract

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 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. 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. 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. Reduced levels of GYLTL1B and ISPD mRNA associated with increased patient mortality and are the likely cause of αDG hypoglycosylation in ccRCC.

Immunohistochemistry

Kidney Neoplasms - genetics

Prognosis

Humans

Middle Aged

Gene Expression Regulation, Neoplastic

Carcinoma, Renal Cell - genetics

Databases, Genetic

Male

Kidney Neoplasms - metabolism

RNA, Messenger - metabolism

DNA Methylation

Neoplasm Grading

Aged, 80 and over

Adult

Female

Membrane Proteins - metabolism

Glycosyltransferases - genetics

Nucleotidyltransferases - metabolism

Promoter Regions, Genetic

Signal Transduction

Carcinoma, Renal Cell - pathology

Membrane Proteins - genetics

Down-Regulation

RNA, Messenger - genetics

Risk Factors

Computational Biology

Glycosylation

Kidney Neoplasms - mortality

Carcinoma, Renal Cell - metabolism

Carcinoma, Renal Cell - mortality

Glycosyltransferases - metabolism

Nucleotidyltransferases - genetics

Kidney Neoplasms - pathology

Aged

Neoplasm Staging

Details

Title: Subtitle: Downregulation of dystroglycan glycosyltransferases LARGE2 and ISPD associate with increased mortality in clear cell renal cell carcinoma
Creators: Michael R Miller - Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, 6-510 Bowen Science Bldg, Iowa, USA
Deqin Ma - Department of Pathology, University of Iowa Carver College of Medicine, Iowa, USA
James Schappet - Institute for Clinical and Translational Sciences, Iowa, USA
Patrick Breheny - Department of Biostatistics, University of Iowa Carver College of Medicine, Iowa, USA
Sarah L Mott - Holden Comprehensive Cancer Center, Iowa, USA
Nadine Bannick - Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, 6-510 Bowen Science Bldg, Iowa, USA
Eric Askeland - Department of Urology, University of Iowa Carver College of Medicine, Iowa, USA
James Brown - Department of Urology, University of Iowa Carver College of Medicine, Iowa, USA
Michael D Henry - Holden Comprehensive Cancer Center, Iowa, USA. michael-henry@uiowa.edu
Resource Type: Journal article
Publication Details: Molecular cancer, Vol.14(1), pp.141-141
DOI: 10.1186/s12943-015-0416-z
PMID: 26220087
PMCID: PMC4518861
NLM abbreviation: Mol Cancer
ISSN: 1476-4598
eISSN: 1476-4598
Publisher: England
Grant note: T32 GM067795 / NIGMS NIH HHS CA130916 / NCI NIH HHS T32 GM007337 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS R01 CA130916 / NCI NIH HHS
Language: English
Date published: 07/30/2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Pathology; Biostatistics; Radiation Oncology; Urology
Record Identifier: 9983997474202771

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