机构：[1]Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China [2]Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510315, China [3]Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumour Hospital of Yunnan Province), Kunming 650118, China [4]Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China [5]The Third People’s Hospital of Kunming, Kunming 650041, China [6]Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China [7]Department of General Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 中山大学附属第二医院[8]Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 中山大学附属第二医院[9]Cancer Center, Southern Medical University, Guangzhou, Guangdong 510315, China
A previous study revealed that therapeutic miR-26a delivery suppresses tumorigenesis in a murine liver cancer model, whereas we found that forced miR-26a expression increased hepatocellular carcinoma (HCC) cell migration and invasion, which prompted us to characterize the causes and mechanisms underlying enhanced invasion due to ectopic miR-26a expression. Gain-of-function and loss-of-function experiments demonstrated that miR-26a promoted migration and invasion of BEL-7402 and HepG2 cells in vitro and positively modulated matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, and MMP-10 expression. In addition, exogenous miR-26a expression significantly enhanced the metastatic ability of HepG2 cells in vivo. miR-26a negatively regulated in vitro proliferation of HCC cells, and miR-26a overexpression suppressed HepG2 cell tumor growth in nude mice. Further studies revealed that miR-26a inhibited cell growth by repressing the methyltransferase EZH2 and promoted cell migration and invasion by inhibiting the phosphatase PTEN. Furthermore, PTEN expression negatively correlated with miR-26a expression in HCC specimens from patients with and without metastasis. Thus, our findings suggest for the first time that miR-26a promotes invasion/metastasis by inhibiting PTEN and inhibits cell proliferation by repressing EZH2 in HCC. More importantly, our data also suggest caution if miR-26a is used as a target for cancer therapy in the future.
基金：
We thank Prof. Qian Zhao (School of Medicine,
Jiao-Tong University) and Prof. Jeng-Shin Lee (Harvard Gene Therapy
Initiative, Harvard Medical School) for generously providing
plasmids. This work was supported by the National Natural Science
Foundation of China (Grant No. 81872209, 81672689, 81372896, and
81172587, to D. Xiao; Grant No. 81600086 and 81770100, to Y. Sun;
Grant No. 81600488 and 81870602, to X.-L. Lin; Grant No.
81702778, to J.S. Jia), the Natural Science Foundation of Guangdong
Province of China (Grant No. 2014A030313294 to D. Xiao), the
Science and Technology Planning Project of Guangdong Province of
China (Grant No. 2009B060300008, 2013B060300013 and
2017A010105017, to D. Xiao; Grant No. 2017A030303018, to J.S.
Jia; Grant No. 2015A030302024, to X.-L. Lin), the Applied Basic
Research Foundation of Yunnan Province Science and Technology
Department & Kunming Medical University of China (Grant No.
2018FE001(-249), to W.T. Zhao), the China Postdoctoral Science
Foundation(Grant No. 2015M572338, 2016T90792, 2017M622740
and 2018T110884, to X.-L. Lin) and the Medical Scientific Research
Foundation of Guangdong Province of China (Grant No. A2017420, to
J.S. Jia).
第一作者机构：[1]Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China [2]Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510315, China [3]Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumour Hospital of Yunnan Province), Kunming 650118, China
共同第一作者：
通讯作者：
通讯机构：[1]Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China [2]Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510315, China [4]Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China [9]Cancer Center, Southern Medical University, Guangzhou, Guangdong 510315, China
推荐引用方式(GB/T 7714)：
Wen-Tao Zhao,Xiao-Lin Lin,Yu Liu,et al.miR-26a promotes hepatocellular carcinoma invasion and metastasis by inhibiting PTEN and inhibits cell growth by repressing EZH2.[J].LABORATORY INVESTIGATION.2019,99(10):1484-1500.doi:10.1038/s41374-019-0270-5.
APA：
Wen-Tao Zhao,Xiao-Lin Lin,Yu Liu,Liu-Xin Han,Jing Li...&Dong Xiao.(2019).miR-26a promotes hepatocellular carcinoma invasion and metastasis by inhibiting PTEN and inhibits cell growth by repressing EZH2..LABORATORY INVESTIGATION,99,(10)
MLA：
Wen-Tao Zhao,et al."miR-26a promotes hepatocellular carcinoma invasion and metastasis by inhibiting PTEN and inhibits cell growth by repressing EZH2.".LABORATORY INVESTIGATION 99..10(2019):1484-1500
