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

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

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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Figure 2

CLIC1 upregulation in HCC is associated with vascular invasion, metastasis, and lower survival.

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CLIC1 upregulation in HCC is associated with vascular invasion, metastas...
A total of 89 pairs of HCC (T) and para-tumor (N) liver tissues and 12 pairs of primary and metastatic HCCs were included. IHC scores for CLIC1 (calculated as percentage of positive hepatocytes × IHC intensity [range 0–3]) were determined by an automation system (inForm Advanced Image Analysis Software, version 2.3, PerkinElmer). (A) A pair of representative IHC images of N and T. Scale bar: 100 μm. Dot plots show the comparison between N and T. Upper, 2-tailed Student’s t test; lower, paired t test. ***P < 0.001. (B) Kaplan-Meier survival curves for the 89 cases of HCC with high (IHC score ≥ 200, n = 40) and low (IHC score < 200, n = 49) CLIC1 levels. A log-rank test determined P value. (C) Representative IHC images of paired primary and metastatic tumors. Scale bar: 100 μm. Dot plots: Upper, Mann-Whitney U test; lower, Wilcoxon signed-rank test. **P < 0.01. (D) Violin plot shows the relative CLIC1 mRNA levels (central dots: medians; bold bars: interquartile ranges) in different stages of HCC in a TCGA HCC cohort (n = 370). Statistical analysis was performed by 1-way ANOVA with Tukey’s corrections. TPM, transcripts per kilobase million. (E–G) Kaplan-Meier survival curves generated from 3 TCGA cohorts: HCC (n = 370), PDAC (n = 177), and NSCLC (n = 504). High and low CLIC1 levels were based on the median CLIC1 value for HCC and the optimal P values by log-rank tests for PDAC and NSCLC.