Abstract 964: Circulating biomarker miRNA-150 promotes tumor cell proliferation and progression by targeting SRC kinase signaling inhibitor 1 (SRCIN1) in non-small cell lung cancer

Abstract

Abstract Circulating microRNAs (c-miRNAs) expression ratio (ER) signatures were evaluated as prognostic biomarkers and therapeutic targets in early stage non-small cell lung cancer (NSCLC) patients. In a population study with 171 stage I and II NSCLC patients, the miR-150 and associated ER signature miR27A/miR-150 (ER ≥0.86, HR = 3.92, p = 1.46E-4) were significantly associated with 5-year survival. The upregulated expression of miR-150 was detected in primary tissue samples (n = 245) by miRNA microarray profiling analysis and significantly associated with cancer recurrence (p = 0.027) and overall survival (HR = 0.88, p = 0.04). Ectopic expression of miR-150 in NSCLC H1299, A549, and H2023 cells transfected by miR-150 expression plasmids promoted tumor cell proliferation, tumor cell-induced colony formation and migration/invasion, while blocking the action of miR-150 with a synthetic miR-150 inhibitor or transduction with a miRZip-150 inhibitor expressed by a lentiviral vector significantly inhibited these biological activities. The SRC kinase signaling inhibitor 1 (SRCIN1) was predicted to be a potential target of miR-150 by bioinformatics tools.miR-150-targeted binding and cleavage in the 3’-UTR of SRCIN1 mRNA were confirmed by a novel stem-loop array-reverse transcription-PCR assay. Both SRCIN1 gene and protein expression were significantly downregulated by ectopic expression of miR-150 and upregulated by miR-150 inhibitors in H1299 and H2023 NSCLC cells, as demonstrated by qRT-PCR and Western-blotting assays, respectively. Modulation of key elements in the SRCIN1 signaling pathway by ectopic expression or inhibition of miR-150 were further determined by qRT-PCR and predicted by ingenuity pathway analysis. Our findings suggest that circulating miR-150 and its associated ER signatures could serve as novel prognostic biomarkers for early stage NSCLC and function as an oncogenic miRNA that promotes lung cancer cell proliferation, invasion, and metastasis by direct targeting SRCIN1signaling pathway thus identifying SRCIN1 as a potential therapeutic target. Citation Format: Jing Lin, Liren Zhang, Yuanqing Ye, Taro Oba, Emanuela Gentile, Emanuela Gentile, Jing Wang, Yang Zhao, Jian Gu, Ignacio Wistuba, Jack A. Roth, Xifeng Wu, Lin Ji. Circulating biomarker miRNA-150 promotes tumor cell proliferation and progression by targeting SRC kinase signaling inhibitor 1 (SRCIN1) in non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 964.