Abstract #242: MUC1, a new Hypoxia Inducible Factor-1 (HIF1) target gene, is an actor in renal clear-cell carcinoma

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO MUC1, an O -glycoprotein membrane-bound mucin, is overexpressed in renal clear-cell carcinomas (RCC) with correlation to two major prognostic factors, TNM stage and nuclear Furhman grade. The main renal carcinogenetic pathway is the HIF (Hypoxia Inducible Factor) pathway. By immunohistochemistry, we showed that HIF-1\#945; and MUC1 were significantly overexpressed in metastatic RCC group vs non-metastatic RCC group. Our hypotheses were that MUC1 is regulated by HIF-1 under hypoxia and that MUC1 may play a role in renal tumor progression. Using different renal cell models and either siRNA assays targeting HIF-1\#945; or YC-1, a HIF-1 pharmacological inhibitor, we observed that induction of MUC1 expression under hypoxia at mRNA, transcriptional and protein levels was HIF-dependent. Site-directed mutagenesis of two putative hypoxia responsive elements inside MUC1 promoter showed that these cis -elements were functional. ChIP and gel shift assays showed a direct interaction between HIF-1\#945; and MUC1 promoter. Using a rat kidney model of ischemia/reperfusion, we confirmed in vivo that clamping renal pedicle for 1 hour followed by 2 hours of reperfusion induced MUC1 overepression at mRNA and protein levels compared to control rat kidneys. Furthermore, invalidation of MUC1 by shRNA technique induced a significant reduction of invasive properties and migratory properties of renal cancer cells under hypoxia. Altogether these results demonstrate that i) MUC1 is a target gene of hypoxia pathway ii) by a HIF-1\#945; dependent mechanism and iii) MUC1 plays a role in invasive and migratory properties of RCC tumor cells. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 242.