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

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.

• Authors: 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
• Journal: Oncogene (Oncogene) Vol. 38 Issue 26 Pg. 5113-5126 (06 2019) ISSN: 1476-5594 [Electronic] England
• PMID: 30867567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KRT14 protein, human
• KRT6A protein, human
• Keratin-14
• Keratin-6
• Recombinant Fusion Proteins

Topics

• Animals
• Carcinogenesis (genetics, pathology)
• Carcinoma, Squamous Cell (genetics, pathology)
• Cell Dedifferentiation (genetics)
• Humans
• Keratin-14 (genetics, physiology)
• Keratin-6 (genetics, physiology)
• Male
• Mice
• Mice, Nude
• Mouth Neoplasms (genetics, pathology)
• NIH 3T3 Cells
• Neoplasm Invasiveness
• Neoplastic Stem Cells (metabolism, physiology)
• Recombinant Fusion Proteins (genetics)
• Tumor Cells, Cultured