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Research Paper|Volume 14, Issue 12|pp 5250—5270

TRPM7 via calcineurin/NFAT pathway mediates metastasis and chemotherapeutic resistance in head and neck squamous cell carcinoma

Tsung-Ming Chen1,2, Chih-Ming Huang3,4, Ming-Shou Hsieh5, Chun-Shu Lin6, Wei-Hwa Lee7, Chi-Tai Yeh5,8, Shao-Cheng Liu9
  • 1Department of Otolaryngology-Head and Neck Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
  • 2Department of Otolaryngology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan
  • 3Department of Otolaryngology, Taitung Mackay Memorial Hospital, Taitung City 950408, Taiwan
  • 4Department of Nursing, Tajen University, Yanpu 90741, Pingtung County, Taiwan
  • 5Department of Medical Research and Education, Taipei Medical University - Shuang Ho Hospital, New Taipei City 235, Taiwan
  • 6Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan
  • 7Department of Pathology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan
  • 8Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu City 30015, Taiwan
  • 9Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan
* Equal contribution
Received: January 30, 2022Accepted: June 23, 2022Published: June 29, 2022
https://doi.org/10.18632/aging.204154

Copyright: © 2022 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The exact mechanisms of Head and neck squamous carcinoma (HNSCC) chemoresistance and metastatic transformation remain unclear. In recent decades, members of the transient receptor potential (TRP) channel family have been proposed as potential biomarkers and/or drug targets in cancer treatment. First, in a TCGA cohort of HNSCC, TRPM7 is highly expressed in cancer tissues, especially the expression in invasive cancer tissues is statistically significant (p>0.001). In GEO and TCGA cohort, patients with high expression of TRPM7 and NFATC2 have poor overall survival rates. The expression of TRPM7 and NFATC2 showed a positive correlation. Compared to human normal oral keratinocytes (hNOK), TRPM7 is overexpressed in FaDU, SAS, and TW2.6 cell lines. Similarly, patients with HNSCC exhibited higher TRPM7 expression than non-HNSCC subjects, and this high TRPM7 expression was associated with worse 5-year overall survival. Furthermore, TRPM7 inversely correlated with E-cadherin, but positively correlated with Vimentin, NANOG, and BMI-1 mRNA levels. Consistent with this, we demonstrated the overexpression of TRPM7 in cisplatin-resistant subjects, compared to the cisplatin-sensitive counterparts. Moreover, shRNA-mediated silencing of TRPM7 significantly suppressed the migration, invasion, colony formation, and tumorsphere formation of SAS cells, with associated downregulation of Snail, c-Myc, cyclin D1, SOX2, OCT4, and NANOG proteins expression. Finally, compared with the untreated wild-type SAS cells or cisplatin-treated cells, shTRPM7 alone or in combination with cisplatin significantly inhibited tumorsphere and colony formation. These findings serving as the basis for development of novel therapeutic strategies against metastasis and chemoresistance, while providing new insights into TRPM7 biology and activity in HNSCC.