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MUC1, a New Hypoxia Inducible Factor Target Gene, Is an Actor in Clear Renal Cell Carcinoma Tumor Progression

¹ Institut National de la Santé et de la Recherche Médicale, U837, Jean-Pierre Aubert Research Center, Equipe 5 «Mucines, Différentiation et Cancérogenèse Épithéliales»; ² Pôle de Pathologie, CHRU; ³ Faculté de Médecine, Université de Lille 2; ⁴ Departement de Chirurgie Digestive, CHRU; and ⁵ UMR 8161, Institut de Biologie de Lille, Centre National de la Recherche Scientifique/Universités de Lille 1 et 2/Institut Pasteur de Lille, IFR 142, Lille, France

Requests for reprints: Michaël Perrais, Institut National de la Santé et de la Recherche Médicale, U837, Jean-Pierre Aubert Research Center, Place de Verdun, 59045 Lille cedex, France. Phone: 33-3-20-29-88-57; Fax: 33-3-20-53-85-62; E-mail: michael.perrais{at}inserm.fr.

Key Words: MUC1 • renal carcinoma • hypoxia • invasion • HIF

The hypoxia inducible factor (HIF) signaling pathway is known as the main renal carcinogenetic pathway. MUC1, an O-glycoprotein membrane-bound mucin, is overexpressed in clear renal cell carcinomas (cRCC) with correlation to two major prognostic factors: tumor-node-metastasis stage and nuclear Fürhman grade. We questioned whether there is a direct link between the HIF pathway and MUC1 overexpression in renal tumors. Interestingly, we observed concomitant increase of HIF-1 and MUC1 in metastatic cRCC group versus nonmetastatic cRCC group. Using different renal cell models and small interfering RNA assays targeting either HIF-1 or YC-1, a HIF-1 pharmacologic inhibitor, we showed induction of MUC1 expression under hypoxia by a HIF-dependent mechanism. Chromatin immunoprecipitation assay showed a direct binding of HIF-1 at the MUC1 promoter. In addition, combined site-directed mutagenesis and gel shift assay allowed the identification of two functional putative hypoxia responsive elements at –1488/–1485 and at –1510/–1507 in the 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 increased MUC1 expression. Furthermore, MUC1 knockdown induced significant reduction of invasive and migration properties of renal cancer cells under hypoxia. Altogether, these results show that MUC1 is directly regulated by HIF-1 and affects the invasive and migration properties of renal cancer cells. Thus, MUC1 could serve as a potential therapeutic target in cRCC. [Cancer Res 2009;69(14):5707–15]