MEIS2C and MEIS2D promote tumor progression via Wnt/β-catenin and hippo/YAP signaling in hepatocellular carcinoma

Journal of Experimental & Clinical Cancer Research

Wei Wang¹  Zhaocai Yu²  Xiaochun Xia³  Nanping Ai⁴  Yanxia Bai⁵  Xinyuan Li⁶  Mingyue Li⁶  Guangbo Tang⁷  Fang-E Liu⁸  Ming li⁹  Song lin^1,10  Jing Zhao^1,10  Lei zhang^1,10  Geng chen^1,10  Qingge Zhu^1,10  Lei Guan^1,10  Shi yao^1,10  Xiao Xiao Ding^1,10  Huqin Zhang^1,10  Shanshan Dong^1,10  Bing He^1,10  Shiming Zhang^1,10  Ting Li^1,10 

[1] Department of Immunology, State Key Laboratory of Cancer Biology, Fourth Military Medical University;Department of Medical Oncology. Xijing Hospital, The Fourth Military Medical University;Department of Medical Technology, Xiamen Medical College;Department of Ophthalmology, Chinese PLA General Hospital;Department of Otolaryngology-Head-Neck Surgery, The First Affiliated Hospital, Medical School of Xi’an Jiaotong University;Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania;Medical College, Xiamen University;Medical College, Xi’an Peihua University;School of Electronics and Information Engineering, Xi’an Jiaotong University;The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University;

关键词: HCC;    MEIS2;    Alternative splicing;    Wnt;    Hippo;    CDC-73;   

DOI  :  10.1186/s13046-019-1417-3

来源: DOAJ

【 摘 要 】

Abstract Background MEIS2 has been identified as one of the key transcription factors in the gene regulatory network in the development and pathogenesis of human cancers. Our study aims to identify the regulatory mechanisms of MEIS2 in hepatocellular carcinoma (HCC), which could be targeted to develop new therapeutic strategies. Methods The variation of MEIS2 levels were assayed in a cohort of HCC patients. The proliferation, clone-formation, migration, and invasion abilities of HCC cells were measured to analyze the effects of MEIS2C and MEIS2D (MEIS2C/D) knockdown with small hairpin RNAs in vitro and in vivo. Chromatin immunoprecipitation (ChIP) was performed to identify MEIS2 binding site. Immunoprecipitation and immunofluorescence assays were employed to detect proteins regulated by MEIS2. Results The expression of MEIS2C/D was increased in the HCC specimens when compared with the adjacent noncancerous liver (ANL) tissues. Moreover, MEIS2C/D expression negatively correlated with the prognosis of HCC patients. On the other hand, knockdown of MEIS2C/D could inhibit proliferation and diminish migration and invasion of hepatoma cells in vitro and in vivo. Mechanistically, MESI2C activated Wnt/β-catenin pathway in cooperation with Parafibromin (CDC73), while MEIS2D suppressed Hippo pathway by promoting YAP nuclear translocation via miR-1307-3p/LATS1 axis. Notably, CDC73 could directly either interact with MEIS2C/β-catenin or MEIS2D/YAP complex, depending on its tyrosine-phosphorylation status. Conclusions Our studies indicate that MEISC/D promote HCC development via Wnt/β-catenin and Hippo/YAP signaling pathways, highlighting the complex molecular network of MEIS2C/D in HCC pathogenesis. These results suggest that MEISC/D may serve as a potential novel therapeutic target for HCC.

【 授权许可】

Unknown