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

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.