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Activation of TMEM16A Ca(2+)-activated Cl(−) channels by ROCK1/moesin promotes breast cancer metastasis
INTRODUCTION: Transmembrane protein 16A (TMEM16A) is a Ca(2+)-activated chloride channel that plays a role in cancer cell proliferation, migration, invasion, and metastasis. However, whether TMEM16A contributes to breast cancer metastasis remains unknown. OBJECTIVE: In this study, we investigated wh...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463928/ https://www.ncbi.nlm.nih.gov/pubmed/34603794 http://dx.doi.org/10.1016/j.jare.2021.03.005 |
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author | Luo, Shuya Wang, Hui Bai, Lichuan Chen, Yiwen Chen, Si Gao, Kuan Wang, Huijie Wu, Shuwei Song, Hanbin Ma, Ke Liu, Mei Yao, Fan Fang, Yue Xiao, Qinghuan |
author_facet | Luo, Shuya Wang, Hui Bai, Lichuan Chen, Yiwen Chen, Si Gao, Kuan Wang, Huijie Wu, Shuwei Song, Hanbin Ma, Ke Liu, Mei Yao, Fan Fang, Yue Xiao, Qinghuan |
author_sort | Luo, Shuya |
collection | PubMed |
description | INTRODUCTION: Transmembrane protein 16A (TMEM16A) is a Ca(2+)-activated chloride channel that plays a role in cancer cell proliferation, migration, invasion, and metastasis. However, whether TMEM16A contributes to breast cancer metastasis remains unknown. OBJECTIVE: In this study, we investigated whether TMEM16A channel activation by ROCK1/moesin promotes breast cancer metastasis. METHODS: Wound healing assays and transwell migration and invasion assays were performed to study the migration and invasion of MCF-7 and T47D breast cancer cells. Western blotting was performed to evaluate the protein expression, and whole-cell patch clamp recordings were used to record TMEM16A Cl(−) currents. A mouse model of breast cancer lung metastasis was generated by injecting MCF-7 cells via the tail vein. Metastatic nodules in the lung were assessed by hematoxylin and eosin staining. Lymph node metastasis, overall survival, and metastasis-free survival of breast cancer patients were assessed using immunohistochemistry and The Cancer Genome Atlas dataset. RESULTS: TMEM16A activation promoted breast cancer cell migration and invasion in vitro as well as breast cancer metastasis in mice. Patients with breast cancer who had higher TMEM16A levels showed greater lymph node metastasis and shorter survival. Mechanistically, TMEM16A promoted migration and invasion by activating EGFR/STAT3/ROCK1 signaling, and the role of the TMEM16A channel activity was important in this respect. ROCK1 activation by RhoA enhanced the TMEM16A channel activity via the phosphorylation of moesin at T558. The cooperative action of TMEM16A and ROCK1 was supported through clinical findings indicating that breast cancer patients with high levels of TMEM16A/ROCK1 expression showed greater lymph node metastasis and poor survival. CONCLUSION: Our findings revealed a novel mechanism underlying TMEM16A-mediated breast cancer metastasis, in which ROCK1 increased TMEM16A channel activity via moesin phosphorylation and the increase in TMEM16A channel activities promoted cell migration and invasion. TMEM16A inhibition may be a novel strategy for treating breast cancer metastasis. |
format | Online Article Text |
id | pubmed-8463928 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-84639282021-10-01 Activation of TMEM16A Ca(2+)-activated Cl(−) channels by ROCK1/moesin promotes breast cancer metastasis Luo, Shuya Wang, Hui Bai, Lichuan Chen, Yiwen Chen, Si Gao, Kuan Wang, Huijie Wu, Shuwei Song, Hanbin Ma, Ke Liu, Mei Yao, Fan Fang, Yue Xiao, Qinghuan J Adv Res Pharmaceutical Science INTRODUCTION: Transmembrane protein 16A (TMEM16A) is a Ca(2+)-activated chloride channel that plays a role in cancer cell proliferation, migration, invasion, and metastasis. However, whether TMEM16A contributes to breast cancer metastasis remains unknown. OBJECTIVE: In this study, we investigated whether TMEM16A channel activation by ROCK1/moesin promotes breast cancer metastasis. METHODS: Wound healing assays and transwell migration and invasion assays were performed to study the migration and invasion of MCF-7 and T47D breast cancer cells. Western blotting was performed to evaluate the protein expression, and whole-cell patch clamp recordings were used to record TMEM16A Cl(−) currents. A mouse model of breast cancer lung metastasis was generated by injecting MCF-7 cells via the tail vein. Metastatic nodules in the lung were assessed by hematoxylin and eosin staining. Lymph node metastasis, overall survival, and metastasis-free survival of breast cancer patients were assessed using immunohistochemistry and The Cancer Genome Atlas dataset. RESULTS: TMEM16A activation promoted breast cancer cell migration and invasion in vitro as well as breast cancer metastasis in mice. Patients with breast cancer who had higher TMEM16A levels showed greater lymph node metastasis and shorter survival. Mechanistically, TMEM16A promoted migration and invasion by activating EGFR/STAT3/ROCK1 signaling, and the role of the TMEM16A channel activity was important in this respect. ROCK1 activation by RhoA enhanced the TMEM16A channel activity via the phosphorylation of moesin at T558. The cooperative action of TMEM16A and ROCK1 was supported through clinical findings indicating that breast cancer patients with high levels of TMEM16A/ROCK1 expression showed greater lymph node metastasis and poor survival. CONCLUSION: Our findings revealed a novel mechanism underlying TMEM16A-mediated breast cancer metastasis, in which ROCK1 increased TMEM16A channel activity via moesin phosphorylation and the increase in TMEM16A channel activities promoted cell migration and invasion. TMEM16A inhibition may be a novel strategy for treating breast cancer metastasis. Elsevier 2021-03-17 /pmc/articles/PMC8463928/ /pubmed/34603794 http://dx.doi.org/10.1016/j.jare.2021.03.005 Text en © 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Pharmaceutical Science Luo, Shuya Wang, Hui Bai, Lichuan Chen, Yiwen Chen, Si Gao, Kuan Wang, Huijie Wu, Shuwei Song, Hanbin Ma, Ke Liu, Mei Yao, Fan Fang, Yue Xiao, Qinghuan Activation of TMEM16A Ca(2+)-activated Cl(−) channels by ROCK1/moesin promotes breast cancer metastasis |
title | Activation of TMEM16A Ca(2+)-activated Cl(−) channels by ROCK1/moesin promotes breast cancer metastasis |
title_full | Activation of TMEM16A Ca(2+)-activated Cl(−) channels by ROCK1/moesin promotes breast cancer metastasis |
title_fullStr | Activation of TMEM16A Ca(2+)-activated Cl(−) channels by ROCK1/moesin promotes breast cancer metastasis |
title_full_unstemmed | Activation of TMEM16A Ca(2+)-activated Cl(−) channels by ROCK1/moesin promotes breast cancer metastasis |
title_short | Activation of TMEM16A Ca(2+)-activated Cl(−) channels by ROCK1/moesin promotes breast cancer metastasis |
title_sort | activation of tmem16a ca(2+)-activated cl(−) channels by rock1/moesin promotes breast cancer metastasis |
topic | Pharmaceutical Science |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463928/ https://www.ncbi.nlm.nih.gov/pubmed/34603794 http://dx.doi.org/10.1016/j.jare.2021.03.005 |
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