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Estrogen receptor-?-miR-1271-SNAI2 feedback loop regulates transforming growth factor-?-induced breast cancer progression.

ABSTRACT: BACKGROUND:Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-? (ER?) or/and progesterone receptor. ER? has been identified to promote the growth of primary breast cancer, however, it can also antagonize signaling pathways that lead to epithelial-mesenchymal transition (EMT), including transforming growth factor-? (TGF-?) signaling. miRNA alteration or dysfunction is involved in cancer development and progression. Although miR-1271 has identified as a tumor suppressor in various cancers, the role of miR-1271 in breast cancer is still limited. METHODS:The effect of miR-1271 on breast cancer progression was investigated both in vitro and in vivo. The EMT-related protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of ER?-miR-1271-SNAI2 feedback loop. RESULTS:miR-1271 suppresses breast cancer progression and EMT phenotype both in vitro and in vivo by targeting SNAI2. Estrogen reverses TGF-?-induced EMT in a miR-1271 dependent manner. Furthermore, ER? transactivates the miR-1271 expression and is also transcriptionally repressed by SNAI2. CONCLUSIONS:Our data uncover the ER?-miR-1271-SNAI2 feedback loop and provide a mechanism to explain the TGF-? network in breast cancer progression.

SUBMITTER: Liu BW

PROVIDER: S-EPMC6397493 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Estrogen receptor-α-miR-1271-SNAI2 feedback loop regulates transforming growth factor-β-induced breast cancer progression.

Liu Bo-Wen BW Yu Zhi-Hao ZH Chen Ao-Xiang AX Chi Jiang-Rui JR Ge Jie J Yu Yue Y Cao Xu-Chen XC

Journal of experimental & clinical cancer research : CR 20190301 1

<h4>Background</h4>Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. ERα has been identified to promote the growth of primary breast cancer, however, it can also antagonize signaling pathways that lead to epithelial-mesenchymal transition (EMT), including transforming growth factor-β (TGF-β) signaling. miRNA alteration or dysfunction is involved i ...[more]

PMID: 30823890

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Project description:Though androgen deprivation therapy is the standard treatment for prostate cancer (PCa), most patients would inevitably progress to castration-resistant prostate cancer (CRPC) which is the main cause of PCa death. Therefore, the identification of novel molecular mechanism regulating cancer progression and achievement of new insight into target therapy would be necessary for improving the benefits of PCa patients. This study aims to study the function and regulatory mechanism of HOTAIR/EZH2/miR-193a feedback loop in PCa progression.MSKCC and TCGA datasets were used to identify miR-193a expression profile in PCa. Cell Counting Kit-8 (CCK-8) assays, colony formation, invasion, migration, flow cytometry, a xenograft model and Gene Set Enrichment Analysis were used to detect and analyze the biological function of miR-193a. Then, we assessed the role of HOTAIR and EZH2 in regulation of miR-193a expression by using plasmid, lentivirus and small interfering RNA (siRNA). Luciferase reporter assays and chromatin immunoprecipitation assays were performed to detect the transcriptional activation of miR-193a by EZH2 and HOTAIR. Further, qRT-PCR and luciferase reporter assays were conducted to examine the regulatory role of miR-193a controlling the HOTAIR expression in PCa. Finally, the correlation between HOTAIR, EZH2 and miR-193a expression were analyzed using In situ hybridization and immunohistochemistry.We found that miR-193a was significantly downregulated in metastatic PCa through mining MSKCC and TCGA datasets. In vitro studies revealed that miR-193a inhibited PCa cell growth, suppressed migration and invasion, and promoted apoptosis; in vivo results demonstrated that overexpression of miR-193a mediated by lentivirus dramatically reduced PCa xenograft tumor growth. Importantly, we found EZH2 coupled with HOTAIR to repress miR-193a expression through trimethylation of H3K27 at miR-193a promoter in PC3 and DU145 cells. Interestingly, further evidence illustrated that miR-193a directly targets HOTAIR showing as significantly reduced HOTAIR level in miR-193a overexpressed cells and tissues. The expression level of miR-193a was inversely associated with that of HOTAIR and EZH2 in PCa.This study firstly demonstrated that miR-193a acted as tumor suppressor in CRPC and the autoregulatory feedback loop of HOTAIR/EZH2/miR-193a served an important mechanism in PCa development. Targeting this aberrantly activated feedback loop may provide a potential therapeutic strategy.

Dataset Information

Estrogen receptor-?-miR-1271-SNAI2 feedback loop regulates transforming growth factor-?-induced breast cancer progression.

Publications

Estrogen receptor-α-miR-1271-SNAI2 feedback loop regulates transforming growth factor-β-induced breast cancer progression.

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