Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma.
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.
The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.
Sung Hee
SH
Lee
The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.
Nicole Kristina
NK
Rigas
The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.
Chang-Ryul
CR
Lee
The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.
April
A
Bang
Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Sonal
S
Srikanth
Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Yousang
Y
Gwack
The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.|UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
Mo K
MK
Kang
The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.|UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
Reuben H
RH
Kim
The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.|UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.|Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
No-Hee
NH
Park
The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.|UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
Ki-Hyuk
KH
Shin
D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D015603:Keratinocytes; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009062:Mouth Neoplasms / Q000473:pathology*; D009154:Mutation; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D000071740:ORAI1 Protein / Q000235:genetics / Q000378:metabolism*; D009959:Oropharyngeal Neoplasms / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D023041:Xenograft Model Antitumor Assays
D007527:Isoenzymes; D050778:NFATC Transcription Factors; C494008:NFATC3 protein, human; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D034741:RNA, Small Interfering; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase
NFAT; OSCC; Orai1; SOCE; cancer stem cells