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Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

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

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

Published in: Molecular Cancer | Issue 1/2015

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Abstract

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 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.

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 αDG hypoglycosylation in ccRCC.
Appendix
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Literature
1.
2.
Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol. 2003;27:612–24.PubMedCrossRef
3.
Gudbjartsson T, Hardarson S, Petursdottir V, Thoroddsen A, Magnusson J, Einarsson GV. Histological subtyping and nuclear grading of renal cell carcinoma and their implications for survival: a retrospective nation-wide study of 629 patients. Eur Urol. 2005;48:593–600.PubMedCrossRef
4.
Sorbellini M, Kattan MW, Snyder ME, Reuter V, Motzer R, Goetzl M, et al. A postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma. J Urol. 2005;173:48–51.PubMedCrossRef
5.
Brannon AR, Reddy A, Seiler M, Arreola A, Moore DT, Pruthi RS, et al. Molecular Stratification of Clear Cell Renal Cell Carcinoma by Consensus Clustering Reveals Distinct Subtypes and Survival Patterns. Genes Cancer. 2010;1:152–63.PubMedCentralPubMedCrossRef
6.
Cancer Genome Atlas Research N. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499:43–9.CrossRef
7.
Ervasti JM, Campbell KP. Membrane organization of the dystrophin-glycoprotein complex. Cell. 1991;66:1121–31.PubMedCrossRef
8.
Ibraghimov-Beskrovnaya O, Ervasti JM, Leveille CJ, Slaughter CA, Sernett SW, Campbell KP. Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature. 1992;355:696–702.PubMedCrossRef
9.
Henry MD, Cohen MB, Campbell KP. Reduced expression of dystroglycan in breast and prostate cancer. Hum Pathol. 2001;32:791–5.PubMedCrossRef
10.
Sgambato A, Migaldi M, Montanari M, Camerini A, Brancaccio A, Rossi G, et al. Dystroglycan expression is frequently reduced in human breast and colon cancers and is associated with tumor progression. Am J Pathol. 2003;162:849–60.PubMedCentralPubMedCrossRef
11.
Sgambato A, Tarquini E, Resci F, De Paola B, Faraglia B, Camerini A, et al. Aberrant expression of alpha-dystroglycan in cervical and vulvar cancer. Gynecol Oncol. 2006;103:397–404.PubMedCrossRef
12.
Akhavan A, Griffith OL, Soroceanu L, Leonoudakis D, Luciani-Torres MG, Daemen A, et al. Loss of cell-surface laminin anchoring promotes tumor growth and is associated with poor clinical outcomes. Cancer Res. 2012;72:2578–88.PubMedCentralPubMedCrossRef
13.
Parberry-Clark C, Bury JP, Cross SS, Winder SJ. Loss of dystroglycan function in oesophageal cancer. Histopathology. 2011;59:180–7.PubMed
14.
Jiang X, Rieder S, Giese NA, Friess H, Michalski CW, Kleeff J. Reduced alpha-dystroglycan expression correlates with shortened patient survival in pancreatic cancer. J Surg Res. 2011;171:120–6.PubMedCrossRef
15.
Moon YW, Rha SY, Zhang X, Jeung HC, Yang WI, Kwon O, et al. Increments of alpha-dystroglycan expression in liver metastasis correlate with poor survival in gastric cancer. J Surg Oncol. 2009;100:459–65.PubMedCrossRef
16.
Coco C, Zannoni GF, Caredda E, Sioletic S, Boninsegna A, Migaldi M, et al. Increased expression of CD133 and reduced dystroglycan expression are strong predictors of poor outcome in colon cancer patients. J Exp Clin Cancer Res. 2012;31:71.PubMedCentralPubMedCrossRef
17.
Shen JG, Xu CY, Li X, Dong MJ, Jiang ZN, Wang J, et al. Dystroglycan is associated with tumor progression and patient survival in gastric cancer. Pathol Oncol Res. 2012;18:79–84.PubMedCrossRef
18.
Sgambato A, Camerini A, Amoroso D, Genovese G, De Luca F, Cecchi M, et al. Expression of dystroglycan correlates with tumor grade and predicts survival in renal cell carcinoma. Cancer Biol Ther. 2007;6:1840–6.PubMedCrossRef
19.
Sgambato A, Camerini A, Genovese G, De Luca F, Viacava P, Migaldi M, et al. Loss of nuclear p27(kip1) and alpha-dystroglycan is a frequent event and is a strong predictor of poor outcome in renal cell carcinoma. Cancer Sci. 2010;101:2080–6.PubMedCrossRef
20.
Singh J, Itahana Y, Knight-Krajewski S, Kanagawa M, Campbell KP, Bissell MJ, et al. Proteolytic enzymes and altered glycosylation modulate dystroglycan function in carcinoma cells. Cancer Res. 2004;64:6152–9.PubMedCrossRef
21.
Bao X, Kobayashi M, Hatakeyama S, Angata K, Gullberg D, Nakayama J, et al. Tumor suppressor function of laminin-binding alpha-dystroglycan requires a distinct beta3-N-acetylglucosaminyltransferase. Proc Natl Acad Sci U S A. 2009;106:12109–14.PubMedCentralPubMedCrossRef
22.
Esser AK, Miller MR, Huang Q, Meier MM, Beltran-Valero De Bernabe D, Stipp CS, et al. Loss of LARGE2 disrupts functional glycosylation of alpha-dystroglycan in prostate cancer. J Biol Chem. 2013;288:2132–42.PubMedCentralPubMedCrossRef
23.
Ervasti JM, Campbell KP. A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J Cell Biol. 1993;122:809–23.PubMedCrossRef
24.
de Bernabe DB, Inamori K, Yoshida-Moriguchi T, Weydert CJ, Harper HA, Willer T, et al. Loss of alpha-dystroglycan laminin binding in epithelium-derived cancers is caused by silencing of LARGE. J Biol Chem. 2009;284:11279–84.PubMedCentralPubMedCrossRef
25.
Manya H, Chiba A, Yoshida A, Wang X, Chiba Y, Jigami Y, et al. Demonstration of mammalian protein O-mannosyltransferase activity: coexpression of POMT1 and POMT2 required for enzymatic activity. Proc Natl Acad Sci U S A. 2004;101:500–5.PubMedCentralPubMedCrossRef
26.
Willer T, Lee H, Lommel M, Yoshida-Moriguchi T, de Bernabe DB, Venzke D, et al. ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. Nat Genet. 2012;44(5):575–80.PubMedCentralPubMedCrossRef
27.
Chiba A, Matsumura K, Yamada H, Inazu T, Shimizu T, Kusunoki S, et al. Structures of sialylated O-linked oligosaccharides of bovine peripheral nerve alpha-dystroglycan. The role of a novel O-mannosyl-type oligosaccharide in the binding of alpha-dystroglycan with laminin. J Biol Chem. 1997;272:2156–62.PubMedCrossRef
28.
Brockington M, Blake DJ, Prandini P, Brown SC, Torelli S, Benson MA, et al. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet. 2001;69:1198–209.PubMedCentralPubMedCrossRef
29.
Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature. 1998;394:388–92.PubMedCrossRef
30.
Yoshida-Moriguchi T, Yu L, Stalnaker SH, Davis S, Kunz S, Madson M, et al. O-mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding. Science. 2010;327:88–92.PubMedCentralPubMedCrossRef
31.
Yoshida-Moriguchi T, Willer T, Anderson ME, Venzke D, Whyte T, Muntoni F, et al. SGK196 is a glycosylation-specific O-mannose kinase required for dystroglycan function. Science. 2013;341:896–9.PubMedCrossRef
32.
Inamori K, Hara Y, Willer T, Anderson ME, Zhu Z, Yoshida-Moriguchi T, et al. Xylosyl- and glucuronyltransferase functions of LARGE in alpha-dystroglycan modification are conserved in LARGE2. Glycobiology. 2013;23:295–302.PubMedCentralPubMedCrossRef
33.
Inamori K, Yoshida-Moriguchi T, Hara Y, Anderson ME, Yu L, Campbell KP. Dystroglycan function requires xylosyl- and glucuronyltransferase activities of LARGE. Science. 2012;335:93–6.PubMedCentralPubMedCrossRef
34.
Hara Y, Kanagawa M, Kunz S, Yoshida-Moriguchi T, Satz JS, Kobayashi YM, et al. Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection. Proc Natl Acad Sci U S A. 2011;108:17426–31.PubMedCentralPubMedCrossRef
35.
36.
Grewal PK, McLaughlan JM, Moore CJ, Browning CA, Hewitt JE. Characterization of the LARGE family of putative glycosyltransferases associated with dystroglycanopathies. Glycobiology. 2005;15:912–23.PubMedCrossRef
37.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(pl1).
38.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.PubMedCrossRef
39.
Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994;7:85–90.PubMedCrossRef
40.
Esteller M, Tortola S, Toyota M, Capella G, Peinado MA, Baylin SB, et al. Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res. 2000;60:129–33.PubMed
41.
Eden S, Cedar H. Role of DNA methylation in the regulation of transcription. Curr Opin Genet Dev. 1994;4:255–9.PubMedCrossRef
42.
Huang Q, Miller MR, Schappet J, Henry MD. The Glycosyltransferase LARGE2 is Repressed by Snail and ZEB1 in Prostate Cancer. Cancer Biol Ther. 2014.
43.
44.
Byles V, Zhu L, Lovaas JD, Chmilewski LK, Wang J, Faller DV, et al. SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis. Oncogene. 2012;31:4619–29.PubMedCentralPubMedCrossRef
45.
Sanchez-Tillo E, Lazaro A, Torrent R, Cuatrecasas M, Vaquero EC, Castells A, et al. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene. 2010;29:3490–500.PubMedCrossRef
Metadata
Title
Downregulation of dystroglycan glycosyltransferases LARGE2 and ISPD associate with increased mortality in clear cell renal cell carcinoma
Authors
Michael R. Miller
Deqin Ma
James Schappet
Patrick Breheny
Sarah L. Mott
Nadine Bannick
Eric Askeland
James Brown
Michael D. Henry
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0416-z

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