Actin cytoskeleton remodeling drives epithelial-mesenchymal transition for hepatoma invasion and metastasis

Abstract

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 via inhibiting EMT. KLHL23 binds to actin and suppresses actin polymerization. KLHL23 silencing induced filopodium and lamellipodium formation. Moreover, EMT 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 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 resulted EMT was reversed by either adenosine 5'-triphosphate supplementation or actin polymerization inhibitors. Downregulation 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 the 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 downregulation) 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 open a new door to develop the prevention and treatment strategies for tumor invasion and metastasis. This article is protected by copyright. All rights reserved.

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