Abstract 3986: MicroRNA-155 regulates angiogenesis by targeting Von Hippel-Lindau (VHL) tumor suppressor

Abstract

Abstract Expression of microRNA-155 (miR-155) is frequently up-regulated in various types of human malignancy, including different forms of B cell lymphoma and carcinoma of breast, lung, colon, head/neck, and kidney; however, its role in cancer angiogenesis remains undefined. In this study, we demonstrate the critical role of miR-155 in regulation of angiogenesis through down-regulation of VHL; in addition we show elevated miR-155 levels in breast cancer correlates to high grade and late stage tumor as well as metastasis and poor overall survival. Stable ectopic expression of miR-155 in human umbilical vein endothelial cells induces tube formation in the absence of VEGF; whereas knockdown of miR-155 inhibits tube formation in the presence of VEGF. Further, we identified VHL as a direct target of miR-155. Stable overexpression of miR-155 results in repression of VHL protein; and knockdown of miR-155 rescues VHL expression. Introduction of VHL cDNA lacking 3’ untranslated region abrogates miR-155 induced tube formation. In addition, evaluation of miR-155 expression in primary breast cancers and normal mammary tissues show miR-155 high in 67 of 154 (43.5%) patients with breast cancer as compared to normal breast tissues. Elevated miR-155 is associated with high grade (49/76, 64.5%) versus low grade (18/78, 23.1%) and late stage (37/70, 52.9%) versus early stage (30/84, 35.7%) as well as invasive (53/85, 62.4%) versus non-invasive (14/69, 20.3%) breast carcinoma. Interestingly, miR-155 is also frequently overexpressed in lymph node-positive tumor (i.e., ≥ 10; 20/32, 62.5%) than node-negative (i.e., < 10; 47/122, 38.2%). Furthermore, patients whose tumors express high levels of miR-155 have shorter overall survival than those of tumors with low levels of miR-155. Our findings indicate that miR-155 plays an important role in tumor angiogenesis by targeting VHL and could be a prognostic marker and a critical therapeutic target in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3986. doi:10.1158/1538-7445.AM2011-3986