Molecular Oncology and Endocrinology Research Group, Department of Medical Biology, University of Québec at Trois-Rivières, Trois-Rivières, Québec G9A 5H7, Canada.
J Biol Chem. 2013 Apr 19;288(16):11555-71. doi: 10.1074/jbc.M112.428920. Epub 2013 Feb 28.
Keratins 8 and 18 (K8/18) are simple epithelial cell-specific intermediate filament proteins. Keratins are essential for tissue integrity and are involved in intracellular signaling pathways that regulate cell response to injuries, cell growth, and death. K8/18 expression is maintained during tumorigenesis; hence, they are used as a diagnostic marker in tumor pathology. In recent years, studies have provided evidence that keratins should be considered not only as markers but also as regulators of cancer cell signaling. The loss of K8/18 expression during epithelial-mesenchymal transition (EMT) is associated with metastasis and chemoresistance. In the present study, we investigated whether K8/18 expression plays an active role in EMT. We show that K8/18 stable knockdown using shRNA increased collective migration and invasiveness of epithelial cancer cells without modulating EMT markers. K8/18-depleted cells showed PI3K/Akt/NF-κB hyperactivation and increased MMP2 and MMP9 expression. K8/18 deletion also increased cisplatin-induced apoptosis. Increased Fas receptor membrane targeting suggests that apoptosis is enhanced via the extrinsic pathway. Interestingly, we identified the tight junction protein claudin1 as a regulator of these processes. This is the first indication that modulation of K8/18 expression can influence the phenotype of epithelial cancer cells at a transcriptional level and supports the hypothesis that keratins play an active role in cancer progression.
角蛋白 8 和 18(K8/18)是简单的上皮细胞特异性中间丝蛋白。角蛋白对于组织完整性至关重要,并且参与细胞对损伤、细胞生长和死亡的反应的细胞内信号通路的调节。角蛋白 8/18 的表达在肿瘤发生过程中得以维持;因此,它们被用作肿瘤病理学中的诊断标志物。近年来,研究提供了证据表明,角蛋白不仅应被视为标志物,而且应被视为癌症细胞信号转导的调节剂。上皮-间充质转化(EMT)过程中 K8/18 表达的丧失与转移和化疗耐药性有关。在本研究中,我们研究了 K8/18 表达是否在 EMT 中发挥积极作用。我们表明,使用 shRNA 稳定敲低 K8/18 会增加上皮癌细胞的集体迁移和侵袭性,而不会调节 EMT 标志物。K8/18 耗尽的细胞表现出 PI3K/Akt/NF-κB 的过度激活以及 MMP2 和 MMP9 表达的增加。K8/18 缺失还增加了顺铂诱导的细胞凋亡。Fas 受体膜靶向的增加表明通过外在途径增强了细胞凋亡。有趣的是,我们鉴定了紧密连接蛋白 Claudin1 作为这些过程的调节剂。这是第一个表明调节 K8/18 表达可以在转录水平上影响上皮癌细胞表型的迹象,并支持角蛋白在癌症进展中发挥积极作用的假说。