The Regulatory Mechanism Of MicroRNA In The Process Of Non-small Cell Lung Cancer Tumorigenesis

Non-small cell lung cancer(NSCLC) accounted for 80–85% of total lung cancer cases with extremely high mortality rates, which could be ameliorated by early diagnosis. Activation of KRAS and inactivation of tumor suppressor LKB1/P53 were common gene mutations detected in multiple subtypes of NSCLCs. Concurrence of LKB1/P53 loss with KRAS oncogenic mutations results in higher malignancy of lung cancer. However, the LKB1/P53 related characteristic micro RNAs(mi RNAs) and their contribution to the malignant progression keep unknown.In this study, mi RNAs profiles were elucidated by deep sequencing of both KRASG12 D, KRASG12DP53-/-and KRASG12DLKB1-/- mouse NSCLC tissues. The 30 consistent up-regulated and 24 down-regulated mi RNAs target genes were predicted and then the signal pathway was clustered. The protein-protein interaction analysis was performed for target gene which was continuing up-regulated or down-regulated in NSCLC.Then among the 54 kinds of down-regulated mi RNAs, mi R-199a-5p and mi R-10 a was chosen for further study in NSCLC. We demonstrated that mi R-199a-5p and mi R-10 a was significantly down-regulated in NSCLC samples from both human patients as well as a mouse model. Here, we verified that mi R-199a-5p plays a tumor suppression role via direct targeting of the MAP3K11 gene in NSCLC. P53 regulated mi R-10 a functions as a tumor suppressor in non-small-cell lung carcinoma via TAK1 and WNK3 pathway was also be verified. Tumor protein P53, a transcriptional factor, played an important role in the progression of tumorigenesis. Our results showed that mi R-150 targets the 3’-UTR of P53 and P53 protein promotes the expression of mi R-34 a, mi R-184, mi R-181 a and mi R-148 which affect cell cycle progression. These findings suggest that mi R-150, P53 protein and relevant mi RNAs are members of a regulatory network in NSCLC tumorigenesis.