PDLIM1 Inhibits Tumor Metastasis Through Activating Hippo Signaling in Hepatocellular Carcinoma

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  • Zhao Huang
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Jian‐Kang Zhou
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Kui Wang
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Haining Chen
    Department of Gastrointestinal Surgery,State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University,Chengdu,China
  • Siyuan Qin
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Jiayang Liu
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Maochao Luo
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Yan Chen
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Jingwen Jiang
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Li Zhou
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Lei Zhu
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Juan He
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Jiao Li
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Wenchen Pu
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Yanqiu Gong
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Jianbo Li
    Department of Liver Surgery and Intensive Care Unit,West China Hospital,Sichuan University,Chengdu,China
  • Qin Ye
    Department of Oncology,Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital,School of Medicine,University of Electronic Science and Technology of China,Chengdu,China
  • Dandan Dong
    Department of Pathology,Sichuan Provincial People's Hospital,Chengdu,China
  • Hongbo Hu
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Zongguang Zhou
    Department of Gastrointestinal Surgery,State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University,Chengdu,China
  • Lunzhi Dai
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Canhua Huang
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China
  • Xiawei Wei
    Laboratory of Aging Research and Cancer Drug Target,State Key Laboratory of Biotherapy and Cancer Center,National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University,Chengdu,China
  • Yong Peng
    State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,and West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, and Collaborative Innovation Center for Biotherapy,Chengdu,China

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<jats:sec> <jats:title>Background and Aims</jats:title> <jats:p>Tumor metastasis is a major factor of high recurrence and mortality in hepatocellular carcinoma (HCC), but its underlying mechanism remains elusive. We report that PDZ and LIM domain protein 1 (PDLIM1) is significantly down‐regulated in metastatic human HCC tissues, which predicts unfavorable prognosis, suggesting that PDLIM1 may play an important inhibitory role during HCC metastasis.</jats:p> </jats:sec> <jats:sec> <jats:title>Approach and Results</jats:title> <jats:p>Functional studies indicate that PDLIM1 knockdown induces epithelial‐to‐mesenchymal transition (EMT) of HCC cells, elevates their invasive capacity, and promotes metastasis <jats:italic toggle="yes">in vitro</jats:italic> and <jats:italic toggle="yes">in vivo</jats:italic>, whereas overexpression of PDLIM1 exhibits opposite phenotypes. Mechanistically, PDLIM1 competitively binds to the cytoskeleton cross‐linking protein alpha‐actinin 4 (ACTN4), leading to the disassociation of ACTN4 from F‐actin, thus preventing F‐actin overgrowth. In contrast, loss of PDLIM1 induces excessive F‐actin formation, resulting in dephosphorylation of large tumor suppressor kinase 1 and activation of Yes‐associated protein, thereby promoting HCC metastasis. Moreover, Asn145 (N145) of PDLIM1 is critical for its interaction with ACTN4, and N145A mutation abolishes its regulatory function in Hippo signaling and HCC metastasis.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Our findings indicate that PDLIM1 suppresses HCC metastasis by modulating Hippo signaling, suggesting that PDLIM1 may be a potential prognostic marker for metastatic HCC.</jats:p> </jats:sec>

収録刊行物

  • Hepatology

    Hepatology 71 (5), 1643-1659, 2020-01-21

    Ovid Technologies (Wolters Kluwer Health)

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