Novel K6-K14 keratin fusion enhances cancer stemness and aggressiveness in oral squamous cell carcinoma
| Autor: | Tritium Hwang, Praveen Kumar Korla, Ming-Tsung Lai, Chun Hung Hua, Chia-Ing Jan, Hui-Jye Chen, Chih-Mei Chen, Chung-Ming Lin, Jack Cheng, Jacky Yang, Li-Wen Chen, Stev Chun-Chin Chao, Natini Jinawath, Chia-Chen Wu, Jim Jinn-Chyuan Sheu, Fuu Jen Tsai, Brian Yu-Ting Kuo, Ming Hsui Tsai |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Cancer Research Carcinogenesis Recombinant Fusion Proteins Cell Mice Nude Biology 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Keratin Genetics medicine Tumor Cells Cultured Animals Humans Neoplasm Invasiveness Intermediate filament Molecular Biology Lymph node chemistry.chemical_classification integumentary system Keratin-14 Keratin-6 Cancer Cell Dedifferentiation medicine.disease 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Cancer research Carcinoma Squamous Cell NIH 3T3 Cells Neoplastic Stem Cells Mouth Neoplasms Stem cell Reprogramming |
| Zdroj: | Oncogene. 38(26) |
| ISSN: | 1476-5594 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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