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MiR-1205 functions as a tumor suppressor by disconnecting the synergy between KRAS and MDM4/E2F1 in non-small cell lung cancer

文献类型：期刊论文

作者Yan, Hong1,2; Chen, Xiaoying1; Li, Yu1,2; Fan, Lei1,2; Tai, Yusi1,2; Zhou, Yang1,2; Chen, Yuxiang1; Qi, Xinming1,2; Huang, Ruimin2,3; Ren, Jin1,2
刊名AMERICAN JOURNAL OF CANCER RESEARCH
出版日期2019
卷号9期号:2页码:312-+
关键词KRAS E2F1 MDM4 microRNA oncogene activation inactivator of tumor suppressor genes
ISSN号2156-6976
通讯作者Qi, Xinming(xmqi@cdser.simm.ac.cn) ; Huang, Ruimin(rmhuang@simm.ac.cn) ; Ren, Jin(jren@cdser.simm.ac.cn)
英文摘要Activated KRAS is frequently observed and paralleled by inactivating of tumor suppressors in lung cancer, while the mechanisms remained elusive. Here, our study revealed a microRNA was involved in KRAS overexpression, activation of KRAS signaling and its synergy with inactivating of tumor suppressor genes. miR-1205 was selected by its sequence-dependent inhibition on KRAS and negative clinical correlation with KRAS. A549 and H460 cells carrying mutant KRAS, were sensitive to the growth inhibition and G1/S arrest induced by miR-1205. Target analysis revealed that miR-1205 could simultaneously downregulate the expression levels of MDM4 and E2F1, which were downstream of KRAS and synergistic with KRAS. Silencing of MDM4 or E2F1 inhibited cellular proliferation. MiR-1205 decreased the protein levels of MDM4 and E2F1 via directly binding to the coding sequence of E2F1 and 3'UTR of MDM4. Meanwhile, blocking RAS-MAPK signaling using KRAS siRNA or ERK1/2 inhibitor exerted similar inhibitory effects on MDM4 and E2F1. Forced expression of KRAS partially restored the inhibition of miR-1205 on MDM4 and E2F1. Overexpression of KRAS, MDM4 or E2F1 could partially rescued the growth inhibition of miR-1205 in vitro. More importantly, miR-1205 strongly inhibited the tumor growth of A549 xenografts in nude mice and decreased the protein levels of KRAS, MDM4 and E2F1 in tumor tissues. Together, our study firstly confirmed a potential synergy between KRAS and MDM4/E2F1 which are p53/RB inactivators in non-small cell lung cancer, and identified miR-1205 as a potent destructor of this synergy, making miR-1205 function as a tumor suppressor in vitro and in vivo.
WOS关键词K-RAS ; P53 ; EXPRESSION ; TARGET ; MDMX ; TRANSFORMATION ; MUTATIONS ; MICRORNAS ; PROTEIN ; ARREST
资助项目National Science and Technology Major Project[2015ZX09102005] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020339] ; One Hundred Talent Program of Chinese Academy of Sciences ; Research Fund of Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120163010]
WOS研究方向Oncology
语种英语
WOS记录号WOS:000459916100010
出版者E-CENTURY PUBLISHING CORP
源URL[http://119.78.100.183/handle/2S10ELR8/290301]  
专题新药研究国家重点实验室
通讯作者Qi, Xinming; Huang, Ruimin; Ren, Jin
作者单位1.Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, State Key Lab Drug Res, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yan, Hong,Chen, Xiaoying,Li, Yu,et al. MiR-1205 functions as a tumor suppressor by disconnecting the synergy between KRAS and MDM4/E2F1 in non-small cell lung cancer[J]. AMERICAN JOURNAL OF CANCER RESEARCH,2019,9(2):312-+.
APA Yan, Hong.,Chen, Xiaoying.,Li, Yu.,Fan, Lei.,Tai, Yusi.,...&Ren, Jin.(2019).MiR-1205 functions as a tumor suppressor by disconnecting the synergy between KRAS and MDM4/E2F1 in non-small cell lung cancer.AMERICAN JOURNAL OF CANCER RESEARCH,9(2),312-+.
MLA Yan, Hong,et al."MiR-1205 functions as a tumor suppressor by disconnecting the synergy between KRAS and MDM4/E2F1 in non-small cell lung cancer".AMERICAN JOURNAL OF CANCER RESEARCH 9.2(2019):312-+.

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来源：上海药物研究所

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