miR-196b-5p–mediated downregulation of TSPAN12 and GATA6 promotes tumor progression in non-small cell lung cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-02, Vol.117 (8), p.4347-4357
• Main Authors: Liang, Guang, Meng, Wei, Huang, Xiangjie, Zhu, Wangyu, Yin, Changtian, Wang, Canwei, Fassan, Matteo, Yu, Yun, Kudo, Masahisa, Xiao, Sisi, Zhao, Chengguang, Zou, Peng, Wang, Yumin, Li, Xiaokun, Croce, Carlo M., Cui, Ri
• Format: Article
• Language: English
• Subjects: Animal models; Biological Sciences; Cell adhesion & migration; Cell cycle; Cell migration; Lung cancer; MicroRNAs; miRNA; Non-small cell lung carcinoma; Qk protein; Ribonucleic acid; RNA; RNA-binding protein; Small cell lung carcinoma; Stability analysis; Suppressors; Tumor suppressor genes; Tumors; Xenografts; Xenotransplantation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1917531117

Lung cancer is the leading cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) accounts for over 80% of lung cancer cases. The RNA binding protein, QKI, belongs to the STAR family and plays tumor-suppressive functions in NSCLC. QKI-5 is a major isoform of QKIs and is predominantly expressed in NSCLC. However, the underlying mechanisms of QKI-5 in NSCLC progression remain unclear.We found that QKI-5 regulated microRNA (miRNA), miR-196b-5p, and its expression was significantly upregulated in NSCLC tissues. Up-regulated miR-196b-5p promotes lung cancer cell migration, proliferation, and cell cycle through directly targeting the tumor suppressors, GATA6 and TSPAN12. Both GATA6 and TSPAN12 expressions were down-regulated in NSCLC patient tissue samples and were negatively correlated with miR-196b-5p expression. Mouse xenograft models demonstrated that miR-196b-5p functions as a potent onco-miRNA, whereas TSPAN12 functions as a tumor suppressor in NSCLC in vivo. QKI-5 bound to miR-196b-5p and influenced its stability, resulting in up-regulated miR-196b-5p expression in NSCLC. Further analysis showed that hypomethylation in the promoter region enhanced miR-196b-5p expression in NSCLC. Our findings indicate that QKI-5 may exhibit novel anticancer mechanisms by regulating miRNA in NSCLC, and targeting the QKI5∼miR-196b-5p∼GATA6/TSPAN12 pathway may enable effectively treating some NSCLCs.