Abstract
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.
Highlights
Loss of keratins 8 and 18 (K8/18) is a hallmark of epithelial-mesenchymal transition (EMT), but its role in tumor progression is unclear
Because we have previously shown that Akt isoforms induce reorganization of the intermediate filament (IF) network [20], we analyzed the role of the K8/18 network in PI3K/Akt signaling in the context of cell motility, invasion, and cisplatin-induced apoptosis
Keratin 8 and 18 Knockdown Increases Epithelial Cancer Cell Motility and Invasion without Modulating EMT Markers—The conversion of epithelial cell into mesenchymal cell involves a change in the composition of IF proteins such that epithelial cells lose the expression of keratins and take on the expression of vimentin, a mesenchymal cell-specific IF protein [2]
Summary
Loss of keratins 8 and 18 (K8/18) is a hallmark of epithelial-mesenchymal transition (EMT), but its role in tumor progression is unclear. We identified the tight junction protein claudin 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. Activation of several transcription factors promotes the degradation of extracellular matrix through expression of metalloproteinases (MMPs) and increases resistance to apoptosis All together these changes enhance invasiveness and chemoresistance, making the EMT process a hallmark of tumor progression [1]. A number of keratins are involved in intracellular signaling pathways that regulate response to injuries [6, 7], protein synthesis [8, 9], the cell cycle (8, 10 –12), cell death [13,14,15,16], and cancer progression [17,18,19]. Because we have previously shown that Akt isoforms induce reorganization of the IF network [20], we analyzed the role of the K8/18 network in PI3K/Akt signaling in the context of cell motility, invasion, and cisplatin-induced apoptosis
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