Oncogenic microRNA-411 promotes lung carcinogenesis by directly targeting suppressor genes SPRY4 and TXNIP

Caiyan Zhang,Xiaomin Liu,Lei Ding,Huimin Wang,Yanping Hu,Qiangling Sun,Yanli Li,Xing Zhang

doi:10.1038/s41388-018-0534-3

Abstract

Lung cancer is one of the most common malignant diseases globally, composed of non-small cell lung cancer (NSCLC, 85%) and small cell lung cancer (SCLC, 15%). MicroRNAs (miRNAs) are single-stranded noncoding RNAs having important roles in lung cancer development. miR-411-5p/3p were reported to be increased significantly in human NSCLC tissues and cell lines. Moreover, miR-411-5p/3p overexpression could accelerate cell proliferation and migration, and impede cell apoptosis in NSCLC cell lines. Mechanically, SPRY4 is confirmed a direct target of miR-411-5p/3p. Furthermore, our findings showed that miR-411-5p/3p promoted lung tumor growth in vivo, decreased SPRY4 expression dramatically, and induced EGFR, AKT signaling activation, as well as epithelial–mesenchymal transition (EMT) simultaneously in tumor tissues. In addition, we showed that miR-411-5p also targeted tumor suppressor TXNIP, involved in regulating positively cell cycle progress in SPC-A1 cells rather than in H1299. Whether cell specificity of low TXNIP mRNA level in H1299 is responsible for the different response to cell cycle between H1299 and SPC-A1 would need further explorations. Collectively, these results suggest that miR-411-5p/3p are required for NSCLC development by suppressing SPRY4 and TXNIP; thus, the miR-411-SPRY4-AKT axis might act as a promising target for lung cancer therapy clinically.

Highlights

Lung cancer is the leading cause of death globally and is responsible for higher morbidity among cancers [1]
It was observed that miR-411-5p/3p were upregulated in most human Nonsmall cell lung cancer (NSCLC) cell lines compared with the normal bronchial epithelium cell line HBE135-E6E7 (HBE, Fig. 1c, d)
We used H1299 and SPC-A1 cells stably transfected with miR-411-5p/3p or an empty vector for assessment of the Results from the CCK-8 assay showed that miR-411-5p/ 3p overexpression dramatically promoted cell proliferation of H1299 and SPC-A1 cells (Fig. 2e, f)

Summary

Introduction

Lung cancer is the leading cause of death globally and is responsible for higher morbidity among cancers [1]. As diagnoses are often made when the disease These authors contributed : Caiyan Zhang, Huimin Wang. MiRNAs have critical roles in cell proliferation [6], apoptosis [7], migration [8], stem cell differentiation [9], and the production of cancer stem cell [10, 11]. Such information suggests that miRNAs are involved in tumorigenesis and can be potential targets for drug development. SPRY4 functions as a tumor suppressor downstream of Wnt7A/Fzd signaling in lung cancer, whose overexpression inhibited cell growth with upregulating the tumor suppressor p53 and p21

Methods

Results

Conclusion