Browsing by Author "Fuu Jen Tsai"

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    Novel K6-K14 keratin fusion enhances cancer stemness and aggressiveness in oral squamous cell carcinoma
    (2019-06-27) Fuu Jen Tsai; Ming Tsung Lai; Jack Cheng; Stev Chun Chin Chao; Praveen Kumar Korla; Hui Jye Chen; Chung Ming Lin; Ming Hsui Tsai; Chun Hung Hua; Chia Ing Jan; Natini Jinawath; Chia Chen Wu; Chih Mei Chen; Brian Yu Ting Kuo; Li Wen Chen; Jacky Yang; Tritium Hwang; Jim Jinn Chyuan Sheu; Asia University Taiwan; China Medical University Hospital Taichung; Ming Chuan University; Faculty of Medicine, Ramathibodi Hospital, Mahidol University; National Sun Yat-Sen University Taiwan; China Medical University Taichung; Taichung Hospital
    © 2019, Springer Nature Limited. Keratin intermediate filament (IF) is one component of cellular architectures, which provides necessary mechanical support to conquer environmental stresses. Recent findings reveal its involvement in mechano-transduction and the associated stem cell reprogramming, suggesting the possible roles in cancer development. Here, we report t(12;17)(q13.13;q21.2) chromosomal rearrangement as the most common fusion event in OSCC, resulting in a variety of inter-keratin fusions. Junction site mapping verified 9 in-frame K6-K14 variants, three of which were correlated with lymph node invasion, late tumor stages (T3/T4) and shorter disease-free survival times. When expressed in OSCC cells, those fusion variants disturbed wild-type K14 organization through direct interaction or aggregate formation, leading to perinuclear structure loss and nuclear deformation. Protein array analyses showed the ability of K6-K14 variant 7 (K6-K14/V7) to upregulate TGF-β and G-CSF signaling, which contributed to cell stemness, drug tolerance, and cell aggressiveness. Notably, K6-K14/V7-expressing cells easily adapted to a soft 3-D culture condition in vitro and formed larger, less differentiated tumors in vivo. In addition to the anti-mechanical-stress activity, our data uncover oncogenic functionality of novel keratin filaments caused by gene fusions during OSCC development.