Dataset Information

MiR-137 alleviates doxorubicin resistance in breast cancer through inhibition of epithelial-mesenchymal transition by targeting DUSP4.

ABSTRACT: Acquired resistance to chemotherapy is a major obstacle in breast cancer (BC) treatment. Accumulated evidence has uncovered that microRNAs (miRNAs) are vital regulators of chemoresistance in cancer. Growing studies reveal that miR-137 acts as a suppressor in tumor progression. However, it remains obscure the role of miR-137 in modulating the sensitivity of BC cells to doxorubicin (DOX). In this study, we demonstrate that miR-137 exerts a significant effect on repressing the development of chemoresistance of BC cells in response to DOX via attenuating epithelial-mesenchymal transition (EMT) of tumor cells in vitro and in vivo. MiR-137 overexpression dramatically elevated the sensitivity of BC cells to DOX as well as impaired the DOX-promoted EMT of tumor cells. Mechanistically, miR-137 directly targeted dual-specificity phosphatase 4 (DUSP4) to impact on the EMT and chemoresistance of BC cells upon DOX treatment. Consistently, decreased DUSP4 efficiently enhanced the sensitivity of BC cells to DOX while overexpressed DUSP4 significantly diminished the beneficial effect of miR-137 on BC cells chemoresistance. Moreover, the increased miR-137 heightened the sensitivity of BC cells-derived tumors to DOX through targeting DUSP4 in vivo. Together, our results provide a novel insight into the DOX resistance of BC cells and miR-137 may serve as a new promising therapeutic target for overcoming chemoresistance in BC.

SUBMITTER: Du F

PROVIDER: S-EPMC6892819 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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miR-137 alleviates doxorubicin resistance in breast cancer through inhibition of epithelial-mesenchymal transition by targeting DUSP4.

Du Feiya F Yu Ling L Wu Ying Y Wang Shuqian S Yao Jia J Zheng Xiaoxiao X Xie Shangzhi S Zhang Shufeng S Lu Xuemei X Liu Yu Y Chen Wei W

Cell death & disease 20191204 12

Acquired resistance to chemotherapy is a major obstacle in breast cancer (BC) treatment. Accumulated evidence has uncovered that microRNAs (miRNAs) are vital regulators of chemoresistance in cancer. Growing studies reveal that miR-137 acts as a suppressor in tumor progression. However, it remains obscure the role of miR-137 in modulating the sensitivity of BC cells to doxorubicin (DOX). In this study, we demonstrate that miR-137 exerts a significant effect on repressing the development of chemor ...[more]

PMID: 31801953

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Project description:BackgroundMicroRNA27b-3p (miR-27b) has been reported to be dysregulated in multiple types of human cancer. However, the expression levels, biological roles, and underlying mechanism of miR-27b in tongue squamous cell carcinoma (TSCC) remain to be elucidated.MethodsBioinformatics analyses and quantitative real-time PCR (qRT-PCR) were used to determine miR-27b expression in TSCC tissues and cell lines. The influence of miR-27b overexpression or inhibition on TSCC cell proliferation, migration, and invasion in vitro, and on tumor growth in vivo, was explored via CCK8, colony formation, wound healing, and transwell assays, and in xenograft tumors in nude mice, respectively. Luciferase reporter assays, qRT-PCR, and Western blotting were performed to clarify the potential mechanisms involving miR-27b in TSCC cells.ResultsmiR-27b was significantly downregulated in TSCC tissues and cell lines, and its expression was correlated with cancer status. Overexpression of miR-27b led to diminished proliferation, migration, and invasion, and notably reduced tumor growth in vivo. Bioinformatics analysis followed by luciferase reporter assays demonstrated that miR-27b expression was inversely correlated with that of integrin subunit α5 (ITGA5)and that miR-27b directly bound to the 3'-untranslated region of ITGA5 in TSCC cells. The bioinformatics analysis also indicated that ITGA5 was upregulated in TSCC and that its expression was correlated with epithelial-mesenchymal transition (EMT) and poor prognosis. Moreover, we found that miRNA-27b could reverse ITGA5-induced promotion of TSCC cell proliferation and migration. Finally, we demonstrated that regulation of miR-27b expression in TSCC may result in alterations in the expression of ITGA5 and EMT-related marker genes at the mRNA and protein levels.ConclusionThese results indicate that miR-27b hampers TSCC proliferation and migration via suppressing the EMT process by targeting ITGA5. These findings support consideration of miR-27b/ITGA5 as a valuable marker for the metastatic potential of TSCC, or as a therapeutic target for the treatment of TSCC.

Project description:BackgroundEpithelial-to-mesenchymal transition (EMT) is a key step of the progression of tumor cell metastasis. Recent work has demonstrated some miRNAs play critical roles in EMT. In this study, we focused on the roles of miR-300 in regulating EMT.MethodsThe expression levels of miR-300 were examined in epithelial carcinoma cells that underwent an EMT using quantitative reverse transcription-PCR. The role of miR-300 in EMT was investigated by transfection of the miR-300 mimic or inhibitor in natural epithelial-mesenchymal phenotype cell line pairs and in transforming growth factor (TGF) beta-induced EMT cell models. A luciferase reporter assay and a rescue experiment were conducted to confirm the target gene of miR-300. The efficacy of miR-300 against tumor invasion and metastasis was evaluated both in vitro and in vivo. Correlation analysis between miR-300 expression and the expression levels of its target gene, as well as tumor metastasis was performed in specimens from patients with head and neck squamous cell carcinoma (HNSCC).ResultsMiR-300 was found down-regulated in the HNSCC cells and breast cancer cells that underwent EMT. Ectopic expression of miR-300 effectively blocked TGF-beta-induced EMT and reversed the phenotype of EMT in HN-12 and MDA-MB-231 cells, but inhibition of miR-300 in the epithelial phenotype cells, HN-4 and MCF-7 cells, could induce EMT. The luciferase reporter assay and the rescue assay results showed that miR-300 directly targets the 3'UTR of Twist. Enforced miR-300 expression suppressed cell invasion in vitro and experimental metastasis in vivo. Clinically, miR-300 expression was found inversely correlated with Twist expression and reduced miR-300 was associated with metastasis in patient specimens.ConclusionsDown-regulation of miR-300 is required for EMT initiation and maintenance. MiR-300 may negatively regulate EMT by direct targeting Twist and therefore inhibit cancer cell invasion and metastasis, which implicates miR-300 as an attractive candidate for cancer therapy.

Dataset Information

MiR-137 alleviates doxorubicin resistance in breast cancer through inhibition of epithelial-mesenchymal transition by targeting DUSP4.

Publications

miR-137 alleviates doxorubicin resistance in breast cancer through inhibition of epithelial-mesenchymal transition by targeting DUSP4.

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