Abstract 3131: Prognostic significance of miR-34a and its inverse correlation with c-MET and CDK6 in lung adenocarcinoma

Abstract

Abstract Background: The microRNA(miR)s affect all aspects of cellular physiology including proliferation, apoptosis, development, aging, and metabolism. miR-34a has tumor suppressive role in various human cancers including non-small cell lung cancer (NSCLC). Recently, various targets of miR-34a including c-MET and G1-phase regulators have been reported in NSCLC cell lines. The aim of this study is to determine whether miR-34a is correlated with c-MET and G1 phase regulators such as cyclin dependent kinase (CDK) 4, CDK6 and cyclin D (CCND)1 in human NSCLC and assess the correlation between miR-34a and clinicopathologic characteristics and recurrence free survival (RFS). Material and Methods: In fresh frozen, paired tumor/normal adjacent tissue samples from 58 NSCLC patients underwent curative resection, expressions of miR-34a and c-MET, CDK4/6, and CCND1 were investigated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. Results: There was inverse correlation between miR-34a and c-MET (R = -0.316; P = 0.003) and CDK6 (R = -0.4582; P = 0.004), however, neither CDK4 (P = 0.556) nor CCND1 (P = 0.143). Of 14 patients with low miR-34a, the patients showing high expression of c-MET protein were 12 (85.7%), whereas, in 5 patients with high miR-34a, high expression of c-MET protein was observed in 3 (60.0%). The expression level of miR-34a was significantly lower in the patients with squamous cell histology (P < 0.001) and lymphatic invasion (P = 0.001). The patients expressing high level of miR-34a were significantly associated with a longer RFS (55.6 months; 95% CI, 47.83-63.36 vs 21.6 months; 95% CI, 17.42-25.82, P = 0.020, respectively) for adenocarcinoma subtype. We could not detect any correlation between the c-MET and RFS (P = 0.666), however, adenocarcinoma patients exhibiting low c-MET mRNA and high miR-34a expression had a significantly longer RFS (54.4 months; 95% CI, 44.59-64.20 vs 18.7 months; 95% CI, 8.93-28.42, P = 0.042). Likewise, although CDK6 expression was not associated with RFS (P = 0.601), the adenocarcinomas having low CDK6 mRNA and high miR-34a expression tended to be longer RFS (55.1 months; 95% CI, 46.40-67.73 vs 27.8 months; 95% CI, 23.04-32.56, P = 0.059). In univariate Cox regression analysis, the relative risk (RR) for recurrence for adenocarcinoma patients with low miR-34a expression was 8.1 (95% CI, 1.01-65.58; P = 0.049) as well as with TNM stage, LN involvement, and the presence of lymphatic invasion of 13.6 (95% CI, 2.93-62.64; P = 0.001), 4.2 (95% CI, 1.05-16.76; P = 0.043) and 7.1 (95% CI, 1.46-34.00; P = 0.015), respectively. In multivariate analysis, miR-34a retained its prognostic independency for RFS (RR, 11.5; 95% CI, 1.31-100.68; P = 0.027). Conclusions: We demonstrated the inverse correlation between miR-34a and c-MET and CDK6 in human NSCLC and their prognostic significance for RFS especially in lung adenocarcinoma. Citation Format: Ji Hyung Hong, Kang San Roh, Sung-Suk Suh, Suk Chan Lee, Jae Ho Byun, Myung ah Lee, Jin Hyoung Kang. Prognostic significance of miR-34a and its inverse correlation with c-MET and CDK6 in lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3131. doi:10.1158/1538-7445.AM2015-3131