FSTL1 enhances chemoresistance and maintains stemness in breast cancer cells via integrin β3/Wnt signaling under miR-137 regulation
FSTL1 enhances chemoresistance and maintains stemness in breast cancer cells via integrin β3/Wnt signaling under miR-137 regulation
复制标题
FSTL1 通过 miR-137 调控下的整合素 β 3/Wnt 信号传导增强乳腺癌细胞的化疗耐药性并维持干性
DOI：
10.1080/15384047.2018.1529101
复制
发表时间：
2019-03-04
影响因子：
3.6
通讯作者：
Zhang, Qingyuan
中科院分区：
文献类型：
--
作者：
Cheng, Shaoqiang;Huang, Yuanxi;Zhang, Qingyuan
FSTL1是一种与细胞信号通路调控和多种疾病进展相关的蛋白编码基因。在这项研究中，我们假设FSTL1通过增强干细胞和化疗耐药来增加乳腺癌的肿瘤发生。RT-PCR和免疫组化显示，TNBC中FSTL1 mRNA和蛋白水平明显高于非TNBC标本和乳腺癌细胞系。然后我们发现FSTL1水平在化疗耐药细胞中显著升高。LIVE/DEAD、MTT细胞活力和集落形成实验确实表明，乳腺癌细胞系的CDDP和DOX化疗耐药需要FSTL1。FSTL1过表达导致干细胞生物标志物显著升高，以及乳腺癌细胞增殖。为了确定Wnt/ β -连环蛋白信号通路是否参与观察到的FSTL1效应，我们评估了通路靶点的水平。TOP/FOP闪光、集落形成和肿瘤球形成实验表明，FSTL1通过整合素β 3激活Wnt/ β -catenin信号传导。然后，我们试图鉴定一种调节FSTL1活性的microRNA （miRNA）。荧光素酶检测显示miR-137降低FSTL1 mRNA和蛋白水平。最终，我们的研究结果表明，乳腺癌细胞中存在miR-137/FSTL1/整合素β 3/Wnt/ β -连环蛋白信号轴，可调节干细胞和化疗耐药。
FSTL1 is a protein coding gene associated with cell signaling pathway regulation and the progression of a variety of disorders. In this study, we hypothesized that FSTL1 increases oncogenesis in breast cancer by enhancing stemness and chemoresistance. RT-PCR and IHC revealed significantly higher FSTL1 mRNA and protein levels in TNBC than in non-TNBC specimens and in breast cancer cell lines. We then found that FSTL1 levels were significantly increased in chemoresistant cells. LIVE/DEAD, MTT cell viability and colony formation assays did in fact demonstrate that FSTL1 is required for CDDP and DOX chemoresistance in breast cancer cell lines. FSTL1 overexpression caused significant elevation of stem cell biomarkers, as well as breast cancer cell proliferation. To determine whether the Wnt/beta-catenin signaling pathway is involved in the observed effects of FSTL1, we assessed levels of pathway target. TOP/FOP flash, colony formation, and tumor sphere formation assays indicated that FSTL1 activates Wnt/beta-catenin signaling through integrin beta 3. We then sought to identify a microRNA (miRNA) that regulates FSTL1 activity. Luciferase assays demonstrated that miR-137 reduces FSTL1 mRNA and protein levels. Ultimately, our findings indicate that there is an miR-137/FSTL1/integrin beta 3/Wnt/beta-catenin signaling axis in breast cancer cells that regulates stemness and chemoresistance.