Premium
PDLIM1 Inhibits Tumor Metastasis Through Activating Hippo Signaling in Hepatocellular Carcinoma
Author(s) -
Huang Zhao,
Zhou JianKang,
Wang Kui,
Chen Haining,
Qin Siyuan,
Liu Jiayang,
Luo Maochao,
Chen Yan,
Jiang Jingwen,
Zhou Li,
Zhu Lei,
He Juan,
Li Jiao,
Pu Wenchen,
Gong Yanqiu,
Li Jianbo,
Ye Qin,
Dong Dandan,
Hu Hongbo,
Zhou Zongguang,
Dai Lunzhi,
Huang Canhua,
Wei Xiawei,
Peng Yong
Publication year - 2020
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30930
Subject(s) - hepatocellular carcinoma , metastasis , cancer research , hippo signaling pathway , medicine , carcinoma , signal transduction , oncology , biology , cancer , microbiology and biotechnology
Background and Aims 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. Approach and Results Functional studies indicate that PDLIM1 knockdown induces epithelial‐to‐mesenchymal transition (EMT) of HCC cells, elevates their invasive capacity, and promotes metastasis in vitro and in vivo , 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. Conclusions Our findings indicate that PDLIM1 suppresses HCC metastasis by modulating Hippo signaling, suggesting that PDLIM1 may be a potential prognostic marker for metastatic HCC.