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Novel K6-K14 keratin fusion enhances cancer stemness and aggressiveness in oral squamous cell carcinoma

Oncogene volume 38, pages 5113–5126 (2019)Cite this article

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Abstract

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.

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Acknowledgements

The authors thank technical assistance from Ms. Lesley Lin at China Medical University Hospital and Mr. Ming-Der Pong at National Sun Yatsen University. The authors also thank critical comments from Prof. Mien-Chie Hung at MD Anderson Cancer Center/U.S., Prof. Chung Chang at National Sun Yatsen University/Taiwan, Prof. Ming-Jer Tang at National Cheng Kung University/Taiwan, and Prof. Ka-Lok Ng at Asia University/Taiwan. This study was supported by grants from Ministry of Science and Technology (MOST), Taiwan with numbers: NSC-102-2628-B-039-001-MY3, MOST 103-2314-B-039-009-MY3, and MOST 106-2314-B-110-001-MY3, and the NSYSU-KMU joint research projects: 107-P012 and 105-P021.

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  1. These authors contributed equally: Fuu-Jen Tsai, Ming-Tsung Lai

Authors and Affiliations

  1. Human Genetic Center, China Medical University Hospital, Taichung, 40447, Taiwan

    Fuu-Jen Tsai, Jack Cheng, Stev Chun-Chin Chao, Chih-Mei Chen & Jim Jinn-Chyuan Sheu

  2. School of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan

    Fuu-Jen Tsai & Jim Jinn-Chyuan Sheu

  3. Department of Pathology, Taichung Hospital, Ministry of Health and Welfare, Taichung, 40343, Taiwan

    Ming-Tsung Lai

  4. Institute of Biomedical Sciences, National Sun Yatsen University, Kaohsiung, 80424, Taiwan

    Praveen Kumar Korla, Chia-Chen Wu, Brian Yu-Ting Kuo, Li-Wen Chen, Jacky Yang, Tritium Hwang & Jim Jinn-Chyuan Sheu

  5. School of Medicine, China Medical University, Taichung, 40402, Taiwan

    Hui-Jye Chen

  6. Department of Biotechnology, Ming Chuan University, Taoyuan, 33348, Taiwan

    Chung-Ming Lin

  7. Department of Otolaryngology, China Medical University Hospital, Taichung, 40447, Taiwan

    Ming-Hsui Tsai & Chun-Hung Hua

  8. Department of Pathology, China Medical University Hospital, Taichung, 40447, Taiwan

    Chia-Ing Jan

  9. Program in Translation Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand

    Natini Jinawath

  10. Department of Health and Nutrition Biotechnology, Asia University, Taichung, 41354, Taiwan

    Jim Jinn-Chyuan Sheu

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Tsai, FJ., Lai, MT., Cheng, J. et al. Novel K6-K14 keratin fusion enhances cancer stemness and aggressiveness in oral squamous cell carcinoma. Oncogene 38, 5113–5126 (2019). https://doi.org/10.1038/s41388-019-0781-y

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