NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma
Tumor-initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel r...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/26733 |
| _version_ | 1818023859130990592 |
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| author | Zhi-Jie Xiao Jing Liu Si-Qi Wang Yun Zhu Xu-Yuan Gao Vicky Pui-Chi Tin Jing Qin Jun-Wen Wang Maria Pik Wong |
| author_facet | Zhi-Jie Xiao Jing Liu Si-Qi Wang Yun Zhu Xu-Yuan Gao Vicky Pui-Chi Tin Jing Qin Jun-Wen Wang Maria Pik Wong |
| author_sort | Zhi-Jie Xiao |
| collection | DOAJ |
| description | Tumor-initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals. Mechanistic investigations identified NFATc2 response elements in the 3’ enhancer region of SOX2, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5’ enhancer. Through this axis, oxidative stress induced by cancer drug treatment is attenuated, leading to increased resistance in a mutation-independent manner. Targeting this axis provides a novel approach for the long-term treatment of lung cancer through TIC elimination. |
| first_indexed | 2024-12-10T03:51:01Z |
| format | Article |
| id | doaj.art-1c68b7b949b346c6b5843405f58ee1a4 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T03:51:01Z |
| publishDate | 2017-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-1c68b7b949b346c6b5843405f58ee1a42022-12-22T02:03:14ZengeLife Sciences Publications LtdeLife2050-084X2017-07-01610.7554/eLife.26733NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinomaZhi-Jie Xiao0https://orcid.org/0000-0001-6365-7278Jing Liu1Si-Qi Wang2Yun Zhu3Xu-Yuan Gao4Vicky Pui-Chi Tin5Jing Qin6Jun-Wen Wang7Maria Pik Wong8https://orcid.org/0000-0003-4028-926XDepartment of Pathology, The University of Hong Kong, Hong Kong, Hong KongDepartment of Pathology, The University of Hong Kong, Hong Kong, Hong KongDepartment of Pathology, The University of Hong Kong, Hong Kong, Hong KongDepartment of Pathology, The University of Hong Kong, Hong Kong, Hong KongDepartment of Pathology, The University of Hong Kong, Hong Kong, Hong KongDepartment of Pathology, The University of Hong Kong, Hong Kong, Hong KongSchool of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong KongDepartment of Health Sciences Research AND Center for Individualized Medicine, Mayo Clinic, Scottsdale, United States; Department of Biomedical Informatics, Arizona State University, Scottsdale, United StatesDepartment of Pathology, The University of Hong Kong, Hong Kong, Hong KongTumor-initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals. Mechanistic investigations identified NFATc2 response elements in the 3’ enhancer region of SOX2, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5’ enhancer. Through this axis, oxidative stress induced by cancer drug treatment is attenuated, leading to increased resistance in a mutation-independent manner. Targeting this axis provides a novel approach for the long-term treatment of lung cancer through TIC elimination.https://elifesciences.org/articles/26733NFATc2tumor-initiating cellsSOX2ALDH1A1 |
| spellingShingle | Zhi-Jie Xiao Jing Liu Si-Qi Wang Yun Zhu Xu-Yuan Gao Vicky Pui-Chi Tin Jing Qin Jun-Wen Wang Maria Pik Wong NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma eLife NFATc2 tumor-initiating cells SOX2 ALDH1A1 |
| title | NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma |
| title_full | NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma |
| title_fullStr | NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma |
| title_full_unstemmed | NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma |
| title_short | NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma |
| title_sort | nfatc2 enhances tumor initiating phenotypes through the nfatc2 sox2 aldh axis in lung adenocarcinoma |
| topic | NFATc2 tumor-initiating cells SOX2 ALDH1A1 |
| url | https://elifesciences.org/articles/26733 |
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