Dataset Information

ZNF281-miR-543 Feedback Loop Regulates Transforming Growth Factor-?-Induced Breast Cancer Metastasis.

ABSTRACT: Breast cancer is the most common malignancy, and metastasis is the main cause of cancer-associated mortality in women worldwide. Transforming growth factor-? (TGF-?) signaling, an inducer of epithelial-to-mesenchymal transition (EMT), plays an important role in breast cancer metastasis. Abnormal expression of miR-543 is associated with tumorigenesis and progression of various human cancers; however, the knowledge about the role of miR-543 in breast cancer metastasis is still unknown. In this study, we demonstrated that miR-543 inhibits the EMT-like phenotype and TGF-?-induced breast cancer metastasis both in vitro and in vivo by targeting ZNF281. ZNF281 transactivates the EMT-related transcription factor ZEB1 and Snail. Furthermore, both ZEB1 and Snail can transcriptionally suppress miR-543 expression. Taken together, our data uncover the ZNF281-miR-543 feedback loop and provide a mechanism to extend the understanding of TGF-? network complexity.

SUBMITTER: Ji W

PROVIDER: S-EPMC7281305 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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ZNF281-miR-543 Feedback Loop Regulates Transforming Growth Factor-β-Induced Breast Cancer Metastasis.

Ji Wei W Mu Qiang Q Liu Xiang-Yu XY Cao Xu-Chen XC Yu Yue Y

Molecular therapy. Nucleic acids 20200521

Breast cancer is the most common malignancy, and metastasis is the main cause of cancer-associated mortality in women worldwide. Transforming growth factor-β (TGF-β) signaling, an inducer of epithelial-to-mesenchymal transition (EMT), plays an important role in breast cancer metastasis. Abnormal expression of miR-543 is associated with tumorigenesis and progression of various human cancers; however, the knowledge about the role of miR-543 in breast cancer metastasis is still unknown. In this stu ...[more]

PMID: 32512343

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Project description:Background: Breast cancer is the most common malignancy, and approximately 70% of breast cancers are estrogen receptor-α (ERα) positive. The anti-estrogen tamoxifen is a highly effective and commonly used treatment for patients with ER+ breast cancer. However, 30% of breast cancer patients fail adjuvant tamoxifen therapy and most of metastatic breast cancer patients develop tamoxifen resistance. Although increasing evidence suggests that microRNA (miRNA) dysregulation influences tamoxifen sensitivity, the mechanism of the cross-talk between miRNA and ERα signaling remains unclear. miR-575 has been reported to be involved in carcinogenesis and progression, however, the role of miR-575 in breast cancer remains limited. The aim of this study was to understand the mechanism of miR-575 in breast cancer tamoxifen resistance. Method: RT-qPCR was employed to assess miR-575 expression in breast cancer tissues and cell lines. The association of miR-575 expression with overall survival in patients with breast cancer was evaluated with KM plotter. Additionally, the effects of miR-575 on breast cancer proliferation and tamoxifen sensitivity were investigated both in vitro and in vivo. Bioinformatic analyses and luciferase reporter assays were performed to validate CDKN1B and BRCA1 as direct targets of miR-31-5p. The ERα binding sites in the miR-575 promoter region was validated with ChIP and luciferase assays. ERα interactions with CDKN1B, cyclin D1 or BRCA1 were determined by IP analysis, and protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Results: miR-575 levels were higher in ER+ breast cancer than in ER- breast cancer and patients with high miR-575 expression had a significantly poorer outcome than those with low miR-575 expression. ERα bound the miR-575 promoter to activate its transcription, and tamoxifen treatment downregulated miR-575 expression in ER+ breast cancer. Overexpression of miR-575 decreased tamoxifen sensitivity by targeting CDKN1B and BRCA1. CDKN1B and BRCA1 were both able to antagonize ERα activity by inhibiting ERα nuclear translocation and interaction with cyclin D1. Furthermore, miR-575 expression was found to be upregulated in ER+ breast cancer cell with acquired tamoxifen resistance, whereas depletion of miR-575 partially re-sensitized these cells to tamoxifen by regulation of CDKN1B. Conclusions: Our data reveal the ERα-miR-575-CDKN1B feedback loop in ER+ breast cancer, suggesting that miR-575 can be used as a prognostic biomarker in patients with ER+ breast cancer, as well as a predictor or a promising target for tamoxifen sensitivity.

Project description:BACKGROUND:Angiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis. METHODS:The expression levels of FUS, circ_002136, miR-138-5p, SOX13, and SPON2 were determined using quantitative real-time PCR (qRT-PCR) and western blot. Transient cell transfection was performed using the Lipofectamine 3000 reagent. The RNA-binding protein immunoprecipitation (RNA-IP) and the RNA pull-down assays were used to detect the interaction between FUS and circ_002136. The dual-luciferase reporter assay system was performed to detect the binding sites of circ_002136 and miR-138-5p, miR-138-5p and SOX13. The chromatin immunoprecipitation (ChIP) assays were used to examine the interactions between transcription factor SOX13 and its target proteins . RESULTS:We demonstrated that down-regulation of FUS or circ_002136 dramatically inhibited the viability, migration and tube formation of U87 glioma-exposed endothelial cells (GECs). MiR-138-5p was down-regulated in GECs and circ_002136 functionally targeted miR-138-5p in an RNA-induced silencing complex (RISC). Inhibition of circ_002136, combined with the restoration of miR-138-5p, robustly reduced the angiogenesis of GECs. As a target gene of miR-138-5p, SOX13 was overexpressed in GECs and was proved to be involved in circ_002136 and miR-138-5p-mediated angiogenesis in gliomas. In addition, we found that SOX13 was directly associated with and activated the SPON2 promoter, thereby up-regulating the expression of SPON2 at the transcriptional level. Knockdown of SPON2 suppressed the angiogenesis in GECs. More important, SOX13 activated the FUS promoter and increased its expression, forming a feedback loop. CONCLUSION:Our data suggests that the feedback loop of FUS/circ_002136/miR-138-5p/SOX13 played a crucial role in the regulation of angiogenesis in glioma. This also provides a potential target and an alternative strategy for combined glioma therapy.

Dataset Information

ZNF281-miR-543 Feedback Loop Regulates Transforming Growth Factor-?-Induced Breast Cancer Metastasis.

Publications

ZNF281-miR-543 Feedback Loop Regulates Transforming Growth Factor-β-Induced Breast Cancer Metastasis.

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