Abstract
Nuclear factor of activated T cells (NFATc1-c4), a family of transcription factors, is involved in many biological processes by regulating various downstream target genes. However, their role in cancer progression remains controversial. We here report that NFATc3 is the dominant isoform of NFAT in human oral epithelial cells, and its expression was increased in a stepwise manner during the progression of oral/oropharyngeal squamous cell carcinoma (OSCC). More importantly, NFATc3 was highly enriched in self-renewing cancer stem-like cells (CSCs) of OSCC. Increased expression of NFATc3 was required for the maintenance of CSC self-renewal, as NFATc3 inhibition suppressed tumor sphere formation in OSCC cells. Conversely, ectopic NFATc3 expression in non-tumorigenic immortalized oral epithelial cells resulted in the acquisition of self-renewal and increase in CSC phenotype, such as enhanced ALDH1HIGH cell population, mobility and drug resistance, indicating the functional role of NFATc3 in the maintenance of CSC phenotype. NFATc3 expression also converted the non-tumorigenic oral epithelial cells to malignant phenotypes. Mechanistic investigations further reveal that NFATc3 binds to the promoter of OCT4, a stemness transcription factor, for its activation, thereby promoting CSC phenotype. Moreover, suppression of OCT4 abrogated CSC phenotype in the cell with ectopic NFATc3 overexpression and OSCC, and ectopic OCT4 expression sufficiently induced CSC phenotype. Our study indicates that NFATc3 plays an important role in the maintenance of cancer stemness and OSCC progression via novel NFATc3-OCT4 axis, suggesting that this axis may be a potential therapeutic target for OSCC CSCs.
Highlights
oropharyngeal squamous cell carcinoma (OSCC), a common malignant tumor of the head and neck is the 6th most common cancer worldwide [1]
Having established that increased NFATc3 is associated with OSCC progression, we investigated whether ectopic NFATc3 expression confers malignant cell growth traits on non-tumorigenic immortalized oral www.oncotarget.com epithelial cells
Our findings reveal for the first time that NFATc3OCT4 signaling is a novel molecular axis for cancer stemness of OSCC
Summary
OSCC, a common malignant tumor of the head and neck is the 6th most common cancer worldwide [1]. Incidence of oral cancer among young adults has been alarmingly elevated [2, 3], indicating that OSCC is an emerging public health concern. Welldefined lesions, such as leukoplakia that is histologically classified as dysplastic or non-dysplastic leukoplakia, often precede OSCC. Early-stage tumors can www.oncotarget.com usually be managed through surgery and radiotherapy. A combination of chemotherapy and radiation therapy is very effective in treating early-stage tumor; its therapeutic effect on advanced tumors remains poorly [6], urgently demanding new directions in therapeutics
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