Abstract 3482: Hypoxia induces translational regulation of lymphangiogenic growth factors

Abstract

Abstract Hypoxia is a major condition for induction of angiogenesis during tumor development, nevertheless its role in lymphangiogenesis remain unclear. In this study, we investigate the role of hypoxia in the translational regulation of lymphangiogenic growth factors. The majority of cellular stresses such as hypoxia leads to an inhibition of mRNA translation in cell by the classical cap-dependent mechanism. However, several mRNAs are translated by an alternative mechanism mediated by internal ribosome entry sites (IRESs) located in their 5’ untranslated regions. We found IRES elements in mRNAs of lymphangiogenic growth factors such as VEGFA and FGF2, and demonstrated that hypoxia is able to activate IRES-mediated mRNA translation both in vitro and in vivo. Interestingly, our recent data demonstrated a strong induction of VEGFA and FGF2 IRES activities in vivo in pancreas adenocarcinoma CAPAN-1, that correlates with development of hypoxia area and lymphangiogenesis in primary tumors. Such an activation is not observed with the viral EMCV IRES used as a control, indicating a translational activation in response to tumoral hypoxia could be specific of angiogenic/lymphangiogenic factors IRESs. We are interested in the translational control of more specific of lymphangiogenic growth factors, VEGFC and VEGFD. We've shown, in CAPAN-1 model, that VEGFC and VEGFD translation correlates with hypoxia area development in vivo. To determine the presence of IRESs in VEGFC and -D mRNAs, we cloned the 5’ untranslated regions of murine and human VEGF-C and -D mRNAs in bicistronic lentivectors. First data suggest the presence of an IRES VEGFC and -D mRNAs. In further investigations, our purpose is to demonstrate that the process of IRES-dependent translation plays a pivotal role in the hypoxic response, and should lead to induction of lymphangiogenic factors, including VEGFC and VEGFD. Thus, cell proteins able to activate IRESs, called IRES trans-acting factors (ITAFs), would be crucial protagonists in the lymphangiogenesis process and potential taget for anti-angiogenic therapy. 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 3482. doi:10.1158/1538-7445.AM2011-3482