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Open Access Publications from the University of California

Role of Orai1 in Oral Cancer

  • Author(s): Lee, Sung Hee
  • Advisor(s): Park, No-Hee
  • Shin, Ki-Hyuk
  • et al.

Oral cancer is the�6th�most common cancer�worldwide, and more than 30,000 Americans are diagnosed with oral cancer each year. The 5-year survival rate for this group of cancers has been about 50%, despite advances in surgery, radiation, and chemotherapy. In addition to premature death associated with oral cancer, the severe morbidity from cancer treatment makes oral cancer a major public health concern. Thus, although there has been in depth studies for understanding the molecular pathogenesis of oral cancer, further studies of the understanding of the cancer etiology, development, progress and recurrences are warranted. Recent studies have shown that cancer cells, including oral cancer, contain a small population of cancer stem cells (CSCs or alternatively cancer initiating cells) associated with drug resistance, metastasis and recurrence of the cancer. Therefore, CSCs might be strategically plausible targets for cancer therapies. More recently, many studies indicated that the suppression of Orai1 can diminish malignant phenotypes of cancer cells. Although Orai1 is known as a key calcium channel for store-operated Ca2+�entry, the underlying mechanism by which Orai1 regulates cancer progression remains unknown. Here we demonstrate that 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 further induced malignant transformation and self-renewal capacity, ALDH1HIGH cell population, increased. Conversely, inhibition of Orai1 suppressed tumorigenic and CSC phenotype in OSCC, indicating that Orai1could 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. Antagonist of NFAT signaling also decreases CSC phenotype, implying the functional importance of Orai1/NFAT axis in OSCC CSC regulation. Moreover, Orai1-induced cytokines in HOK-16B/Orai1 cells were commonly upregulated in CSCs and enhanced important CSC phenotypes, i.e., self-renewal in OSCC. Subset of these CSC-specific cytokines were regulated by NFAT signaling, and partially rescued CSC phenotype in Orai1 inactivated OSCC, which suggests a possible role of cytokines in regulating CSC through Orai1-NFAT signaling. This study identifies Orai1 as a novel molecular determinant for OSCC progression by enhancing cancer stemness, suggesting that inhibition of Orai1-NFAT signaling may offer an effective therapeutic modality against OSCC.

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