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CLIC1 recruits PIP5K1A/C to induce cell-matrix adhesions for tumor metastasis
Jei-Ming Peng, … , Ming-Chin Yu, Sen-Yung Hsieh
Jei-Ming Peng, … , Ming-Chin Yu, Sen-Yung Hsieh
Published October 20, 2020
Citation Information: J Clin Invest. 2021;131(1):e133525. https://doi.org/10.1172/JCI133525.
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Research Article Cell biology Hepatology Article has an altmetric score of 1

CLIC1 recruits PIP5K1A/C to induce cell-matrix adhesions for tumor metastasis

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Abstract

Membrane protrusion and adhesion to the extracellular matrix, which involves the extension of actin filaments and formation of adhesion complexes, are the fundamental processes for cell migration, tumor invasion, and metastasis. How cancer cells efficiently coordinate these processes remains unclear. Here, we showed that membrane-targeted chloride intracellular channel 1 (CLIC1) spatiotemporally regulates the formation of cell-matrix adhesions and membrane protrusions through the recruitment of PIP5Ks to the plasma membrane. Comparative proteomics identified CLIC1 upregulated in human hepatocellular carcinoma (HCC) and associated with tumor invasiveness, metastasis, and poor prognosis. In response to migration-related stimuli, CLIC1 recruited PIP5K1A and PIP5K1C from the cytoplasm to the leading edge of the plasma membrane, where PIP5Ks generate a phosphatidylinositol 4,5-bisphosphate–rich (PIP2-rich) microdomain to induce the formation of integrin-mediated cell-matrix adhesions and the signaling for cytoskeleon extension. CLIC1 silencing inhibited the attachment of tumor cells to culture plates and the adherence and extravasation in the lung alveoli, resulting in suppressed lung metastasis in mice. This study reveals what we believe is an unrecognized mechanism that spatiotemporally coordinates the formation of both lamellipodium/invadopodia and nascent cell-matrix adhesions for directional migration and tumor invasion/metastasis. The unique traits of upregulation and membrane targeting of CLIC1 in cancer cells make it an excellent therapeutic target for tumor metastasis.

Authors

Jei-Ming Peng, Sheng-Hsuan Lin, Ming-Chin Yu, Sen-Yung Hsieh

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