HIF-2αregulates CD44 to promote cancer stem cell activation in triple-negative breast cancer via PI3K/AKT/mTOR signaling

• 作者: Hui Zhang Jie Bai Li-Jun Jin Wei-Bin Chen Xiao-Ning Kang Xiao-Yu Zhang Zun-Yi Wang
• 来源期刊: 世界干细胞杂志:英文版(电子版)
• 学科: 医学
• 关键词: BREAST CANCER Hypoxia-inducible factor-2α CANCER stem cells CD44
• 年，卷（期）: 2020,（1）
• 页码范围: 87-99
• 页数: 13页
• 分类号: R73

摘要

BACKGROUND Breast cancer is a common malignant tumor that seriously threatens women’s health.Breast cancer stem cell(CSC)-like cell population may be the main factor for breast cancer metastasis.Therefore,targeted therapy for CSCs has great potential significance.Hypoxia-inducible factor is a transcription factor widely expressed in tumors.Studies have shown that down-regulation of the hypoxia signaling pathway inhibits tumor stem cell self-renewal and increases the sensitivity of stem cells to radiotherapy and chemotherapy mediated by hypoxiainducible factor-2α(HIF-2α).However,the specific mechanism remains unclear and further research is necessary.AIM To investigate the effect of HIF-2α down-regulation on stem cell markers,microsphere formation,and apoptosis in breast cancer cell line MDA-MB-231 under hypoxia and its possible mechanism.METHODS Immunohistochemistry was used to detect the expression of HIF-2α and CD44 in triple-negative breast cancer(TNBC) and non-TNBC tissues.Double-labeling immunofluorescence was applied to detect the co-expression of HIF-2α and CD44 in MDA-MB-231 cells and MCF-7 cells.HIF-2α was silenced by RNA interference,and the expression of CD44 and transfection efficiency were detected by real-time fluorescent quantitative PCR.Further,flow cytometry,Td T-mediated X-d UTP nick end labeling,and mammosphere formation assays were used to evaluate the effect of HIF-2α on CSCs and apoptosis.The possible mechanisms were analyzed by Western blot.RESULTS The results of immunohistochemistry showed that HIF-2α was highly expressed in both TNBC and non-TNBC,while the expression of CD44 in different molecular types of breast cancer cells was different.In in vitro experiments,it was found that HIF-2α and CD44 were expressed almost in the same cell.Compared with hypoxia + negative-sequence control,HIF-2α small interfering ribonucleic acid transfection can lower the expression of HIF-2α and CD44 m RNA(P < 0.05),increase the percentage of apoptotic cells(P < 0.05),and resulted in a reduction