AUTHOR=Liu Jing-Hua , Li Wen-Ting , Yang Yue , Qi Yan-Bo , Cheng Yu , Wu Jia-Hui 

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

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.696269

DOI=10.3389/fonc.2021.696269

ISSN=2234-943X

ABSTRACT=<p>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 <italic>in vivo.</italic> Significantly, hypoxia could enhance IC<sub>50</sub> value of PTX in breast cancer cells. IC<sub>50</sub> 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<sub>50</sub> 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<sub>50</sub> value of PTX in breast cancer cells, in which the overexpression of HIF-2α could rescue the miR-526b-3p-inhibited IC<sub>50</sub> 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.</p>