Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Carcinogenesis. 2012 May;33(5):986-95. doi: 10.1093/carcin/bgs115. Epub 2012 Mar 1.
Chloride intracellular channel (CLIC) 4 is a member of a redox-regulated, metamorphic multifunctional protein family, first characterized as intracellular chloride channels. Current knowledge indicates that CLICs participate in signaling, cytoskeleton integrity and differentiation functions of multiple tissues. In metabolically stressed skin keratinocytes, cytoplasmic CLIC4 is S-nitrosylated and translocates to the nucleus where it enhances transforming growth factor-β (TGF-β) signaling by protecting phospho-Smad 2 and 3 from dephosphorylation. CLIC4 expression is diminished in multiple human epithelial cancers, and the protein is excluded from the nucleus. We now show that CLIC4 expression is reduced in chemically induced mouse skin papillomas, mouse and human squamous carcinomas and squamous cancer cell lines, and the protein is excluded from the nucleus. The extent of reduction in CLIC4 coincides with progression of squamous tumors from benign to malignant. Inhibiting antioxidant defense in tumor cells increases S-nitrosylation and nuclear translocation of CLIC4. Adenoviral-mediated reconstitution of nuclear CLIC4 in squamous cancer cells enhances TGF-β-dependent transcriptional activity and inhibits growth. Adenoviral targeting of CLIC4 to the nucleus of tumor cells in orthografts inhibits tumor growth, whereas elevation of CLIC4 in transgenic epidermis reduces de novo chemically induced skin tumor formation. In parallel, overexpression of exogenous CLIC4 in squamous tumor orthografts suppresses tumor growth and enhances TGF-β signaling. These results indicate that CLIC4 suppresses the growth of squamous cancers, that reduced CLIC4 expression and nuclear residence detected in cancer cells is associated with the altered redox state of tumor cells and the absence of detectable nuclear CLIC4 in cancers contributes to TGF-β resistance and enhances tumor development.
氯离子细胞内通道 (CLIC) 4 是一个氧化还原调控的、形态多样的多功能蛋白家族的成员，最初被描述为细胞内氯离子通道。目前的知识表明，CLICs 参与多种组织的信号转导、细胞骨架完整性和分化功能。在代谢应激的皮肤角质形成细胞中，细胞质 CLIC4 被 S-亚硝基化，并转移到细胞核内，通过保护磷酸化 Smad 2 和 3 免受去磷酸化，增强转化生长因子-β（TGF-β）信号。在多种人类上皮癌中，CLIC4 的表达减少，并且该蛋白被排除在细胞核之外。我们现在表明，CLIC4 的表达在化学诱导的小鼠皮肤乳头瘤、小鼠和人鳞状细胞癌及鳞状癌细胞系中降低，并且该蛋白被排除在细胞核之外。CLIC4 减少的程度与鳞状肿瘤从良性到恶性的进展相一致。在肿瘤细胞中抑制抗氧化防御会增加 CLIC4 的 S-亚硝基化和核转位。腺病毒介导的核 CLIC4 在鳞状癌细胞中的重建增强了 TGF-β 依赖性转录活性并抑制了生长。腺病毒将 CLIC4 靶向肿瘤细胞的核内可抑制肿瘤生长，而转基因表皮中 CLIC4 的升高可减少新发性化学诱导的皮肤肿瘤形成。平行地，过表达外源性 CLIC4 在鳞状肿瘤异体移植中抑制肿瘤生长并增强 TGF-β 信号。这些结果表明，CLIC4 抑制鳞状癌的生长，在癌细胞中检测到的 CLIC4 表达减少和核内居留与肿瘤细胞的改变氧化还原状态有关，并且在癌症中未检测到可检测的核 CLIC4 有助于 TGF-β 抵抗并增强肿瘤发展。
