J Cancer 2017; 8(9):1704-1716. doi:10.7150/jca.16961
MiR-146b-5p functions as a suppressor miRNA and prognosis predictor in non-small cell lung cancer
1. Department of Lung Cancer Surgery
2. Tianjin key laboratory of lung cancer metastasis and tumor microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Anshan Road No.154, Heping District, Tianjin 300052, China
# Contributed equally in this work.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. However, science has not yet been able to substantially improve the prognosis of lung cancer patients. Accumulating evidence suggests that microRNAs (miRNAs) are key players in the regulation of tumor development and metastasis. Expression of six miRNAs previously shown to play roles in tumor development (miR-146b-5p, miR-128b, miR-21, miR-221, miR-34a, and Let-7a) in other tumor types was examined using real-time RT-PCR in 78 specimens of NSCLC. The results revealed that patients with low expression of miR-146b-5p had significant shorter median and mean survival time than those with high miR-146b-5p expression (33.00 and 30.44 months versus 42.0 and 36.90 months, respectively; log-rank test P=0.048), thus low miR-146b-5p expression level was associated with poor prognosis in NSCLC patients. Univariate Cox hazard regression analysis demonstrated that miR-146b-5p expression levels tended to be a significant prognostic indicator of NSCLC (adjusted hazard ratio=0.482, 95% CI: 1.409- 29.593, P=0.016). Multivariate Cox proportional hazard regression analysis showed that miR-146b-5p expression levels were an independent prognostic factor for NSCLC patients (hazard ratio=0.259, 95% CI: 0.083-0.809, P=0.020). Furthermore, the effects of miR-146b-5p and miR-146b-3p on NSCLC cell growth and invasion in vitro were investigated. Our findings demonstrate that ectopic expression of miR-146b-5p suppressed cell proliferation, clonogenicity, migration/ invasion and also induced G1 arrest in vitro, but did not induce cell apoptosis; whereas enforced expression of miR-146b-3p did not have a significant effect on cell growth and metastasis. Further experiments indicated that miR-146b-5p could reduce mRNA levels of MMP16 and TRAF6 in vitro and was negatively related to the expression of TRAF6 in human NSCLC tissues. In a mouse model, Ago-miR-146b-5p could significantly inhibit the growth of lung cancer xenografts in nude mice. In conclusion, our findings demonstrate that miR-146b-5p functions as a suppressor miRNA and prognosis predictor in NSCLC.
Keywords: miR-146b-5p, non-small cell lung cancer, prognosis, and metastasis
Li Y, Zhang H, Dong Y, Fan Y, Li Y, Zhao C, wang C, Liu J, Li X, Dong M, Liu H, Chen J. MiR-146b-5p functions as a suppressor miRNA and prognosis predictor in non-small cell lung cancer. J Cancer 2017; 8(9):1704-1716. doi:10.7150/jca.16961. Available from http://www.jcancer.org/v08p1704.htm