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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 Ca(2+) 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 m...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5190020/ https://www.ncbi.nlm.nih.gov/pubmed/27259269 http://dx.doi.org/10.18632/oncotarget.9755 |
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author | Lee, Sung Hee Rigas, Nicole Kristina Lee, Chang-Ryul Bang, April Srikanth, Sonal Gwack, Yousang Kang, Mo K. Kim, Reuben H. Park, No-Hee Shin, Ki-Hyuk |
author_facet | Lee, Sung Hee Rigas, Nicole Kristina Lee, Chang-Ryul Bang, April Srikanth, Sonal Gwack, Yousang Kang, Mo K. Kim, Reuben H. Park, No-Hee Shin, Ki-Hyuk |
author_sort | Lee, Sung Hee |
collection | PubMed |
description | Emerging evidence indicates that Orai1, a key calcium channel for store-operated Ca(2+) 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 ALDH1(HIGH) 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. |
format | Online Article Text |
id | pubmed-5190020 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-51900202017-01-05 Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma Lee, Sung Hee Rigas, Nicole Kristina Lee, Chang-Ryul Bang, April Srikanth, Sonal Gwack, Yousang Kang, Mo K. Kim, Reuben H. Park, No-Hee Shin, Ki-Hyuk Oncotarget Research Paper Emerging evidence indicates that Orai1, a key calcium channel for store-operated Ca(2+) 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 ALDH1(HIGH) 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. Impact Journals LLC 2016-06-01 /pmc/articles/PMC5190020/ /pubmed/27259269 http://dx.doi.org/10.18632/oncotarget.9755 Text en Copyright: © 2016 Lee et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Lee, Sung Hee Rigas, Nicole Kristina Lee, Chang-Ryul Bang, April Srikanth, Sonal Gwack, Yousang Kang, Mo K. Kim, Reuben H. Park, No-Hee Shin, Ki-Hyuk Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma |
title | Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma |
title_full | Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma |
title_fullStr | Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma |
title_full_unstemmed | Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma |
title_short | Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma |
title_sort | orai1 promotes tumor progression by enhancing cancer stemness via nfat signaling in oral/oropharyngeal squamous cell carcinoma |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5190020/ https://www.ncbi.nlm.nih.gov/pubmed/27259269 http://dx.doi.org/10.18632/oncotarget.9755 |
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