Abstract B221: Hmga2 furthers lung adenocarcinoma progression through function as a competing endogenous RNA.

Abstract

Abstract Lung adenocarcinoma is the most widespread cancer type worldwide. As the majority of patients are diagnosed with metastatic disease, it is vital to understand that biological basis of adenocarcinoma progression. Hmga2 is among the most over-expressed genes in lung adenocarcinoma, and we have previously shown it is necessary for lung cancer progression in vivo. However, the mechanism of Hmga2-mediated cancer progression is unclear. Here we demonstrate Hmga2 promotes oncogenic transformation by functioning as a competing endogenous RNA (ceRNA) for the let-7 family of microRNAs (miRNAs). First, Hmga2 can promote lung cancer cell transformation independent of its protein-coding function but dependent upon let-7 sites in its 3’ untranslated region. These effects are observed both in vitro and in vivo, where Hmga2 ceRNA activity promotes lung cancer growth and dissemination, impairing survival. Combined analyses of miRNA target prediction and cell line gene expression data suggested the TGF-β co-receptor Tgfbr3 lies downstream of the Hmga2 ceRNA. Follow-up studies demonstrated Hmga2 specifically regulated Tgfbr3 expression through differential recruitment of the miRNA regulatory machinery. This regulation is functionally relevant, as both Tgfbr3 in particular and TGF-β in general are necessary for Hmga2 to promote transformation. To assess the clinical relevance of these experimental findings, we assessed gene expression data from two extensive lung cancer patient gene expression datasets: the Cancer Genome Atlas and the Director's Challenge. Analysis of this gene expression data revealed that HMGA2 and TGFBR3 are coordinately and reciprocally regulated in patients, a necessary prediction of HMGA2 ceRNA function. In total, these results indicate the Hmga2 oncogene functions as both a protein-coding gene and a ceRNA. Such multi-level regulation of gene expression constitutes a novel paradigm by which genes alter cancer development and progression through combined function as both coding proteins and non-coding RNAs. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B221. Citation Format: Madhu S. Kumar, Elena Armenteros-Monterroso, Philip East, Probir Chakravorty, Nik Matthews, Monte M. Winslow, Julian Downward. Hmga2 furthers lung adenocarcinoma progression through function as a competing endogenous RNA. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B221.