Abstract 439: Glycosylation of α-dystroglycan in prostate cancer: Prognostic implications and regulation by LARGE2
Authors: Michael R. Miller, Alison K. Esser, Christine J. Weydert, Melissa M. Meier, Brian J. Smith, Robert L. Vessella, Charles Lynch, Michael B. Cohen, Michael D. Henry
Journal: Cancer Research (2012)

Abstract Cancer cells exhibit altered interactions with their extracellular matrix microenvironment that are thought to underlie tumor progression and metastasis. Dystroglycan (DG) is a receptor for extracellular matrix proteins including laminins and perlecan that consists of a ligand-binding α subunit and a transmembrane β subunit. DG protein expression is reduced in numerous types of cancer, including prostate cancer. Typically DG mRNA expression is not remarkably altered and mutations in the DG gene have not been reported in any cancer to date. We have investigated the basis for reduced DG expression in prostate cancer. Using tissue microarray (n=50; Gleason score 6-8) we show that loss of either α or β DG independently predicts Gleason score. We show that loss of αDG immunostaining in human prostatectomy samples (n=138) trended towards predicting overall mortality independent of grade and stage with an estimated hazard ratio of 1.32 (CI=0.92, 1.89; p=0.1381). Furthermore, analysis of prostate cancer metastases in bone, lung and lymph node shows a near universal loss of αDG immunostaining. Importantly, we observed cases in which αDG is reduced while βDG persisted in serial sections, suggesting that these subunits may be differentially affected. In these studies, we detected αDG using a glycosylation-sensitive antibody IIH6. Therefore, we investigated the basis of altered αDG glycosylation using a series of prostate cancer cell lines. We found that αDG glycosylation is heterogeneous across several prostate cancer cell lines. Importantly, we found that an aggressive derivative of PC-3 cells lacks IIH6 immunoreactivity, but not core αDG protein expression; whereas the bulk PC-3 population is IIH6 positive. We evaluated the relative expression of a panel of glycosyltransferases known to modify αDG in these cell lines and found that loss of IIH6 immunoreactivity is correlated with loss of LARGE2 expression. This result contrasts with previous findings implicating LARGE or iGNT with abnormal glycosylation of αDG in breast and prostate cancer respectively. Reduced expression of LARGE2 is also observed in pancreatic cancer cell lines and is correlated with loss of IIH6 immunoreactivity. We show that LARGE2 is involved in the functional glycosylation of αDG in prostate cancer cells. shRNA-mediated knockdown of LARGE2 in prostate cancer cells does not affect growth rate, but does increase transwell migration across laminin-1 substrate. Our results are the first to implicate loss of LARGE2 expression as a means to explain the loss of appropriate glycosylation of αDG in prostate or other cancers, and indicates that LARGE2 function may modulate prostate cancer progression and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 439. doi:1538-7445.AM2012-439