Mir-34a/C-Dependent Pdgfr-Alpha/Beta Reduction Inhibits Tumorigenesis And Sensitizes Trail-Induced Apoptosis In Lung Cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Lung cancer is the most common cause of cancer death worldwide. Despite years of research, the prognosis for patients with lung cancer remains dismal. The most frequent type, non-small cell lung cancer (NSCLC) (85%), shows an overall five year survival of 15%. Isoforms of platelet-derived growth factor receptor (PDGFR) and its ligand, PDGF, constitute a family of receptors and ligands involved in proliferative and prosurvival signaling within cells. MicroRNAs (miRNAs), a class of ~ 22 nt endogenous RNAs, are important regulators of gene expression and have been implicated in the regulation of critical processes that are deregulated in cancer cells, as proliferation differentiation and apoptosis. Alterations in miRNA expression in cancer have been documented in numerous studies and suggest that miRNAs critically contribute to the cancer cell phenotype. In mammalians, the miR-34 family comprises three processed miRNAs that are encoded by two different genes: miR-34a is encoded by its own transcript, whereas miR-34b and miR-34c share a common primary transcript. In this study we found that miR-34a/c and not miR-34b, suppress the metastatic capacity of NSCLC by targeting platelet-derived growth factor receptor alpha and beta (PDGFR-α and PDGFR-β). We also observed an inverse relation between PDGFR-α/β mRNAs and miR-34a/c expression in lung tumor compared to normal lung samples. Finally, miR34-a/c-dependent PDGFR-α/β suppression or knocking-down of PDGFR-α/β by siRNAs sensitized NSCLC cells to TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis. Taken together our findings could be helpful for future anti-tumor therapy of lung cancer. Citation Format: Young-Jun Jeon, Gerard J. Nuovo, Justin Midddleton, Pooja Joshi, Natalya Nazaryan, Gianpiero Di Leva, Giulia Romano, Melissa Crawford, Patrick Nana-Sinkam, Michela Garofalo, Carlo M. Croce. MiR-34a/c-dependent PDGFR-α/β reduction inhibits tumorigenesis and sensitizes TRAIL-induced apoptosis in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-244. doi:10.1158/1538-7445.AM2013-LB-244