Premium
Actin cytoskeleton remodeling drives epithelial‐mesenchymal transition for hepatoma invasion and metastasis in mice
Author(s) -
Peng JeiMing,
Bera Rabindranath,
Chiou ChihYung,
Yu MingChin,
Chen TseChin,
Chen ChiaWei,
Wang TsungRui,
Chiang WanLing,
Chai ShinPei,
Wei Yongkun,
Wang Huamin,
Hung MienChie,
Hsieh SenYung
Publication year - 2018
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.29678
Subject(s) - microbiology and biotechnology , actin cytoskeleton , invadopodia , actin remodeling , epithelial–mesenchymal transition , cytoskeleton , biology , metastasis , lamellipodium , cancer research , cell migration , gene silencing , chemistry , cancer , cell , genetics , biochemistry , gene
High invasiveness is a hallmark of human hepatocellular carcinoma (HCC). Large tumors predict invasion and metastasis. Epithelial‐mesenchymal transition (EMT) is crucial for cancer invasion and metastasis. However, the mechanisms whereby large tumors tend to undergo EMT remain unclear. We conducted a subgenome‐wide screen and identified KLHL23 as an HCC invasion suppressor by inhibiting EMT. KLHL23 binds to actin and suppresses actin polymerization. KLHL23 silencing induced filopodium and lamellipodium formation. Moreover, EMT was suppressed by KLHL23 through its action on actin dynamics. Traditionally, actin cytoskeleton remodeling is downstream of EMT reprogramming. It is therefore intriguing to ask why and how KLHL23 inversely regulates EMT. Activation of actin cytoskeleton remodeling by either KLHL23 silencing or treatment with actin cytoskeleton modulators augmented cellular hypoxic responses in a cell‐density–dependent manner, resulting in hypoxia‐inducible factor (HIF) and Notch signals and subsequent EMT. Environmental hypoxia did not induce EMT unless actin cytoskeleton remodeling was simultaneously activated and only when cells were at high density. The resulting EMT was reversed by either adenosine 5′‐triphosphate supplementation or actin polymerization inhibitors. Down‐regulation of KLHL23 was associated with invasion, metastasis, and poor prognosis of HCC and pancreatic cancer. Correlations of tumor size with EMT and inverse association of expression of KLHL23 with HIF/Notch signals were further validated in patient‐derived xenograft HCCs in mice. Conclusion: Simultaneously activation of actin cytoskeleton remodeling by intrinsic (such as KLHL23 down‐regulation) or microenvironment cues is crucial for cell‐density–dependent and hypoxia‐mediated EMT, providing a mechanistic link between large tumor size and invasion/metastasis. Our findings provide a means of developing the prevention and treatment strategies for tumor invasion and metastasis. (H epatology 2018;67:2226‐2243).