Abstract
Keratins are intermediate filament (IF) proteins with major functions in controlling/maintaining cell morphology and stiffness. Recent studies indicated possible involvement of keratin IFs in cancer developments. In our previous study, we have identified the existence of keratin fusions between KRT6 and KRT14 genes in oral squamous cell carcinoma (OSCC), and patients with the history of chewing betel nut showed higher frequency to harbor such fusions in their tumor tissues. In this study, we studied bio-functional roles of a major keratin fusion isotype K6-K14/V7, which correlated with bigger tumor size, in cell migration and invasion. We established a tet-off inducible gene expression system in OSCC cells. After gene being turned on, K6-K14/V7 formed a peripheral-dominant network that subsequently up-regulated genes related to actin filament remodeling via mechano-transduction. Actin-associated protrusion at cell leading edge was also increased by K6-K14/V7 to enhance cell migration and invasion. Interestingly, the desmosome junction was found to be dramatically reduced, leading to loss of cell-cell contact and stemness formation via epithelial-mesenchymal transition (EMT). The K6-K14/V7-expressing cells showed reduced drug sensitivity toward 5-FU and cisplatin treatment, and formed more colonies in vitro and bigger tumors in vivo. This study uncovers new functions/definitions for keratin IF in cancer development, Mechanisms revealed by this study can help us to design new strategies for new drug development and clinical treatments.
Citation Format: Jim J. Sheu, Brian Y. Kuo, Chia-Cheng Wu, Jacky Yang, Chih-Mei Chen. Functional roles of KRT6-KRT14 fusion variant 7 in desmosome remodeling and cell spreading/migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4504.