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MiR-526b-3p Attenuates Breast Cancer Stem Cell Properties and Chemoresistance by Targeting HIF-2α/Notch Signaling

Chemoresistance is a severe clinical challenge in breast cancer. Hypoxia and cancer stem cells (CSCs) contribute to the paclitaxel (PTX) resistance, but the molecular mechanisms are still elusive. MicorRNAs (miRNA) have been considered a promising therapeutic strategy in various cancers. Here, we id...

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Autores principales: Liu, Jing-Hua, Li, Wen-Ting, Yang, Yue, Qi, Yan-Bo, Cheng, Yu, Wu, Jia-Hui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8733566/
https://www.ncbi.nlm.nih.gov/pubmed/35004266
http://dx.doi.org/10.3389/fonc.2021.696269
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author Liu, Jing-Hua
Li, Wen-Ting
Yang, Yue
Qi, Yan-Bo
Cheng, Yu
Wu, Jia-Hui
author_facet Liu, Jing-Hua
Li, Wen-Ting
Yang, Yue
Qi, Yan-Bo
Cheng, Yu
Wu, Jia-Hui
author_sort Liu, Jing-Hua
collection PubMed
description Chemoresistance is a severe clinical challenge in breast cancer. Hypoxia and cancer stem cells (CSCs) contribute to the paclitaxel (PTX) resistance, but the molecular mechanisms are still elusive. MicorRNAs (miRNA) have been considered a promising therapeutic strategy in various cancers. Here, we identified the crucial function of miR-526b-3p in regulating PTX resistance and CSC properties. Our data demonstrated that miR-526b-3p mimic repressed the cell viability of breast cancer cells. The counts of Edu-positive cells were reduced by miR-526b-3p in breast cancer cells. Meanwhile, the apoptosis of breast cancer cells was induced by miR-526b-3p. Tumorigenicity analysis in the nude mice confirmed that miR-526b-3p attenuated the breast cancer cell growth in vivo. Significantly, hypoxia could enhance IC(50) value of PTX in breast cancer cells. IC(50) value of PTX was induced in breast cancer mammospheres. The hypoxia-inducible factor 2α (HIF-2α) expression was enhanced, but miR-526b-3p expression was repressed under hypoxia in breast cancer cells. Also, breast cancer mammospheres presented high HIF-2α expression and low miR-526b-3p expression. The inhibition of miR-526b-3p enhanced the IC(50) value of PTX in breast cancer cells. MiR-526b-3p inhibitor enhanced the colony formation counts of PTX-treated breast cancer cells. The treatment of miR-526b-3p mimic suppressed the sphere formation counts of breast cancer cells and inhibited ALDH1 and Nanog expression. MiR-526b-3p was able to target HIF-2α in the cells. The overexpression enhanced but miR-526b-3p reduced the IC(50) value of PTX in breast cancer cells, in which the overexpression of HIF-2α could rescue the miR-526b-3p-inhibited IC(50) value of PTX. Overexpression of HIF-2α reversed miR-526b-3p-regulated apoptosis, colony formation ability, and ALDH1 and Nanog expression in the cells. Interestingly, the overexpression of HIF-2α induced but miR-526b-3p repressed the expression of HIF-2α, Hey2, and Notch in PTX-treated breast cancer cells, while HIF-2α could reverse the effect of miR-526b-3p. In conclusion, miR-526b-3p attenuated breast cancer stem cell properties and chemoresistance by targeting HIF-2α/Notch signaling. MiR-526b-3p may be utilized in the relieving chemoresistance in breast cancer.
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spelling pubmed-87335662022-01-07 MiR-526b-3p Attenuates Breast Cancer Stem Cell Properties and Chemoresistance by Targeting HIF-2α/Notch Signaling Liu, Jing-Hua Li, Wen-Ting Yang, Yue Qi, Yan-Bo Cheng, Yu Wu, Jia-Hui Front Oncol Oncology Chemoresistance is a severe clinical challenge in breast cancer. Hypoxia and cancer stem cells (CSCs) contribute to the paclitaxel (PTX) resistance, but the molecular mechanisms are still elusive. MicorRNAs (miRNA) have been considered a promising therapeutic strategy in various cancers. Here, we identified the crucial function of miR-526b-3p in regulating PTX resistance and CSC properties. Our data demonstrated that miR-526b-3p mimic repressed the cell viability of breast cancer cells. The counts of Edu-positive cells were reduced by miR-526b-3p in breast cancer cells. Meanwhile, the apoptosis of breast cancer cells was induced by miR-526b-3p. Tumorigenicity analysis in the nude mice confirmed that miR-526b-3p attenuated the breast cancer cell growth in vivo. Significantly, hypoxia could enhance IC(50) value of PTX in breast cancer cells. IC(50) value of PTX was induced in breast cancer mammospheres. The hypoxia-inducible factor 2α (HIF-2α) expression was enhanced, but miR-526b-3p expression was repressed under hypoxia in breast cancer cells. Also, breast cancer mammospheres presented high HIF-2α expression and low miR-526b-3p expression. The inhibition of miR-526b-3p enhanced the IC(50) value of PTX in breast cancer cells. MiR-526b-3p inhibitor enhanced the colony formation counts of PTX-treated breast cancer cells. The treatment of miR-526b-3p mimic suppressed the sphere formation counts of breast cancer cells and inhibited ALDH1 and Nanog expression. MiR-526b-3p was able to target HIF-2α in the cells. The overexpression enhanced but miR-526b-3p reduced the IC(50) value of PTX in breast cancer cells, in which the overexpression of HIF-2α could rescue the miR-526b-3p-inhibited IC(50) value of PTX. Overexpression of HIF-2α reversed miR-526b-3p-regulated apoptosis, colony formation ability, and ALDH1 and Nanog expression in the cells. Interestingly, the overexpression of HIF-2α induced but miR-526b-3p repressed the expression of HIF-2α, Hey2, and Notch in PTX-treated breast cancer cells, while HIF-2α could reverse the effect of miR-526b-3p. In conclusion, miR-526b-3p attenuated breast cancer stem cell properties and chemoresistance by targeting HIF-2α/Notch signaling. MiR-526b-3p may be utilized in the relieving chemoresistance in breast cancer. Frontiers Media S.A. 2021-12-23 /pmc/articles/PMC8733566/ /pubmed/35004266 http://dx.doi.org/10.3389/fonc.2021.696269 Text en Copyright © 2021 Liu, Li, Yang, Qi, Cheng and Wu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Liu, Jing-Hua
Li, Wen-Ting
Yang, Yue
Qi, Yan-Bo
Cheng, Yu
Wu, Jia-Hui
MiR-526b-3p Attenuates Breast Cancer Stem Cell Properties and Chemoresistance by Targeting HIF-2α/Notch Signaling
title MiR-526b-3p Attenuates Breast Cancer Stem Cell Properties and Chemoresistance by Targeting HIF-2α/Notch Signaling
title_full MiR-526b-3p Attenuates Breast Cancer Stem Cell Properties and Chemoresistance by Targeting HIF-2α/Notch Signaling
title_fullStr MiR-526b-3p Attenuates Breast Cancer Stem Cell Properties and Chemoresistance by Targeting HIF-2α/Notch Signaling
title_full_unstemmed MiR-526b-3p Attenuates Breast Cancer Stem Cell Properties and Chemoresistance by Targeting HIF-2α/Notch Signaling
title_short MiR-526b-3p Attenuates Breast Cancer Stem Cell Properties and Chemoresistance by Targeting HIF-2α/Notch Signaling
title_sort mir-526b-3p attenuates breast cancer stem cell properties and chemoresistance by targeting hif-2α/notch signaling
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8733566/
https://www.ncbi.nlm.nih.gov/pubmed/35004266
http://dx.doi.org/10.3389/fonc.2021.696269
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