Abstract
Emerging evidence indicates that Orai1, a key calcium channel for store-operated Ca2+ entry, is associated with human cancer. However, the underlying mechanism by which Orai1 regulates cancer progression remains unknown. Here we report that intracellular level of Orai1 is increased in a stepwise manner during oral/oropharyngeal carcinogenesis and highly expressed in cancer stem-like cell (CSC)-enriched populations of human oral/oropharyngeal squamous cell carcinoma (OSCC). Ectopic Orai1 expression converted non-tumorigenic immortalized oral epithelial cells to malignant cells that showed CSC properties, e.g., self-renewal capacity, increased ALDH1HIGH cell population, increased key stemness transcription factors, and enhanced mobility. Conversely, inhibition of Orai1 suppressed tumorigenicity and CSC phenotype of OSCC, indicating that Orai1 could be an important element for tumorigenicity and stemness of OSCC. Mechanistically, Orai1 activates its major downstream effector molecule, NFATc3. Knockdown of NFATc3 in the Orai1-overexpressing oral epithelial cells abrogates the effect of Orai1 on CSC phenotype. Moreover, antagonist of NFAT signaling also decreases CSC phenotype, implying the functional importance of Orai1/NFAT axis in OSCC CSC regulation. Our study identifies Orai1 as a novel molecular determinant for OSCC progression by enhancing cancer stemness, suggesting that inhibition of Orai1 signaling may offer an effective therapeutic modality against OSCC.
Highlights
oropharyngeal squamous cell carcinoma (OSCC) is the sixth most common cancer and an important public health concern worldwide [1]
We report for the first time that Orai1 expression is elevated in a stepwise manner in oral/oropharyngeal carcinogenesis and enriched in OSCC Cancer stem cells (CSCs) populations
Using laser capture microdissection (LCM), we determined the level of Orai1 mRNA in dysplasia and OSCC tissues and found that Orai1 mRNA is increased in OSCC compared to dysplastic tissues (Supplementary Figure 1)
Summary
OSCC is the sixth most common cancer and an important public health concern worldwide [1]. The clinical stage at which the diagnosis is made is the most important prognostic indicator of oral cancer. Identifying the biomarker that allows detection of early stage cellular aberration leading to OSCC tumorigenesis is critically important for reducing www.impactjournals.com/oncotarget of cancer-associated morbidity. CSCs have been isolated from various primary tumors and established cancer cell lines, including OSCC [8, 9]. They are potentially responsible for drug resistance, metastasis, and recurrence of cancers. Advancing our understanding of the molecular properties and signaling pathways unique to OSCC CSCs is crucial for developing a new generation of targeted and effective therapies for oral/oropharyngeal cancer
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