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Restoration of mutant K-Ras repressed miR-199b inhibits K-Ras mutant non-small cell lung cancer progression

Cited 2 time in Web of Science Cited 2 time in Scopus
Authors
Jin, Hua; Jang, Yoonjeong; Cheng, Nian; Li, Qing; Cui, Peng-Fei; Zhou, Zhi-Wei; Jiang, Hu-Lin; Cho, Myung-Haing; Westover, Kenneth D; Tan, Qun-You; Xu, Cheng-Xiong
Issue Date
2019-04-15
Publisher
BioMed Central
Citation
Journal of Experimental & Clinical Cancer Research, 38(1):165
Keywords
miR-199bK-RasNon-small cell lung cancer
Abstract
Background
miRNAs play crucial role in the progression of K-Ras-mutated nonsmall cell lung cancer (NSCLC). However, most studies have focused on miRNAs that target K-Ras. Here, we investigated miRNAs regulated by mutant K-Ras and their functions.

Methods
miRNAs regulated by mutant K-Ras were screened using miRNA arrays. miR-199b expression levels were measured by qRT-PCR. The protein expression levels were measured using Western blot and immunohistochemistry. The effects of miR-199b on NSCLC were examined both in vitro and in vivo by overexpressing or inhibiting miR-199b. DNA methylation was measured by bisulfite sequencing.

Results
An inverse correlation was observed between K-Ras mutation status and miR-199b levels in NSCLC specimens and cell lines. The inhibition of miR-199b stimulated NSCLC growth and metastasis, while restoration of miR-199b suppressed K-Ras mutation-driven lung tumorigenesis as well as K-Ras-mutated NSCLC growth and metastasis. miR-199b inactivated ERK and Akt pathways by targeting K-Ras, KSR2, PIK3R1, Akt1, and Rheb1. Furthermore, we determined that mutant K-Ras inhibits miR-199b expression by increasing miR-199b promoter methylation.

Conclusion
Our findings suggest that mutant K-Ras plays an oncogenic role through downregulating miR-199b in NSCLC and that overexpression of miR-199b is a novel strategy for the treatment of K-Ras-mutated NSCLC.
ISSN
1756-9966
Language
English
URI
http://hdl.handle.net/10371/153246
DOI
https://doi.org/10.1186/s13046-019-1170-7
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Journal Papers (저널논문_수의학과)
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