Abstract A01: Long noncoding RNA H19 regulates growth factor signaling in breast cancer cells

H19 is one of the earliest identified, and the most studied, long noncoding RNAs. H19 gene is submitted to genomic imprinting and expressed only from the maternal allele and has no protein associated to its transcription. It has been proposed that H19 RNA function as a riboregulator. H19 is essential for development regulation but is also associated with carcinogenesis in many organs. However, biological functions and regulatory mechanisms of this conserved non coding RNA remain largely undecipher. Previously, we have shown that H19 is overexpressed in 70% of human breast cancers. In addition, its over-expression promotes cells invasion and angiogenesis. H19, positively regulated by E2F1, promotes cell cycle progression and G1/S transition. Altogether, these data support oncogenic function in breast tumor genesis of H19. Recently, H19 has been showed to be a microRNA precursor of miR-675-5p and miR-675-3p. MicroRNAs are small non-coding RNA that regulate expression of up to 60% of genes. However, miR-675 targets have not yet been identified in breast cancer cells. H19 gene expression is positively regulated by several growth factors, in peculiar hepatocyte growth factor / scatter factor (HGF/SF). HGF/SF stimulates proliferation of epithelial cells and increases both their motility and morphogenesis. In the present study, in order to explain these phenotypes, we have searched for miR-675 targets in breast cancer cells. We demonstrate that H19, through its microRNA miR-675-5p, regulates negatively the expression of ubiquitin ligase E3 proteins: c-Cbl and Cbl-b. Both these proteins are involved in tyrosine kinase receptor degradation. In all breast cancer cells tested, c-Cbl and Cbl-b expression was significantly decreased after H19 or miR-675 over-expression. This downregulation promotes stability of growth factor receptors (EGFR, c-Met) that sustains and amplifies activation of downstream signaling pathways (Akt, MAP-kinase). Furthermore, we have shown that H19 overexpression increases breast cancer cells migration and invasion. Our data demonstrate that H19 gene overexpression increases HGF/SF receptor signaling as well as associated phenotypes. Our work propose a mechanism of action of H19 in breast cancer in increasing cell invasion and metastasis in this organ. H19 could also be involved in the mechanism of tumor resistance to treatment by increasing paracrine phenomena. Citation Format: Constance Vennin, Fatima Dhamani, Nathalie Spruyt, Eric Adriaenssens. Long noncoding RNA H19 regulates growth factor signaling in breast cancer cells. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A01.