Chloride Intracellular Channel Proteins (CLICs) and Malignant Tumor Progression: A Focus on the Preventive Role of CLIC2 in Invasion and Metastasis

SIMPLE SUMMARY: Although chloride intracellular channel proteins (CLICs) have been identified as ion channel proteins, their true functions are still elusive. Recent in silico analyses show that CLICs may be prognostic markers in cancer. This review focuses on CLIC2 that plays preventive roles in malignant cell invasion and metastasis. CLIC2 is secreted extracellularly and binds to matrix metalloproteinase 14 (MMP14), while inhibiting its activity. As a result, CLIC2 may contribute to the development/maintenance of junctions between blood vessel endothelial cells and the inhibition of invasion and metastasis of tumor cells. CLIC2 may be a novel therapeutic target for malignancies. ABSTRACT: CLICs are the dimorphic protein present in both soluble and membrane fractions. As an integral membrane protein, CLICs potentially possess ion channel activity. However, it is not fully clarified what kinds of roles CLICs play in physiological and pathological conditions. In vertebrates, CLICs are classified into six classes: CLIC1, 2, 3, 4, 5, and 6. Recently, in silico analyses have revealed that the expression level of CLICs may have prognostic significance in cancer. In this review, we focus on CLIC2, which has received less attention than other CLICs, and discuss its role in the metastasis and invasion of malignant tumor cells. CLIC2 is expressed at higher levels in benign tumors than in malignant ones, most likely preventing tumor cell invasion into surrounding tissues. CLIC2 is also expressed in the vascular endothelial cells of normal tissues and maintains their intercellular adhesive junctions, presumably suppressing the hematogenous metastasis of malignant tumor cells. Surprisingly, CLIC2 is localized in secretory granules and secreted into the extracellular milieu. Secreted CLIC2 binds to MMP14 and inhibits its activity, leading to suppressed MMP2 activity. CLIC4, on the other hand, promotes MMP14 activity. These findings challenge the assumption that CLICs are ion channels, implying that they could be potential new targets for the treatment of malignant tumors.