Fuu Jen TsaiMing Tsung LaiJack ChengStev Chun Chin ChaoPraveen Kumar KorlaHui Jye ChenChung Ming LinMing Hsui TsaiChun Hung HuaChia Ing JanNatini JinawathChia Chen WuChih Mei ChenBrian Yu Ting KuoLi Wen ChenJacky YangTritium HwangJim Jinn Chyuan SheuAsia University TaiwanChina Medical University Hospital TaichungMing Chuan UniversityFaculty of Medicine, Ramathibodi Hospital, Mahidol UniversityNational Sun Yat-Sen University TaiwanChina Medical University TaichungTaichung Hospital2020-01-272020-01-272019-06-27Oncogene. Vol.38, No.26 (2019), 5113-512614765594095092322-s2.0-85062910754https://repository.li.mahidol.ac.th/handle/20.500.14594/50147© 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1038/s41388-019-0781-y