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MicroRNA-221 promotes breast cancer resistance to adriamycin via modulation of PTEN/Akt/mTOR signaling.

ABSTRACT: As a prevalent tumor among women, breast cancer is still an incurable disease due to drug resistance. In this study, we report microRNA-221 to have a significant effect on breast cancer resistance to adriamycin. The microRNA-221 is elevated in tumor tissue compared with nearby nontumor samples, as well as in breast cancer cell line with adriamycin resistance (MCF-7/ADR) compared to its parental line (MCF-7) and the normal breast epithelial cell line (MCF-10A). Enforced level of microRNA-221 promotes cancer resistance to adriamycin, which in turn sustains cell survival and exacerbates malignant formation. Reciprocally, the silence of microRNA-221 in cancer cells augments the sensitivity to chemotherapy, thereby resulting in enhanced apoptosis of MCF-7/ADR cells. Mechanistically, we identify PTEN as a direct target of microRNA-221, which was conversely associated with a microRNA-221 level in breast tumors. The knock-down of PTEN partially reversed the stimulatory role of microRNA-221 in the modulation of the Akt/mTOR signaling. Taken together, these findings suggest microRNA-221 suppresses PTEN transcription and activates Akt/mTOR pathway, which in turn enhances breast cancer resistance to adriamycin and promotes cancer development. Our data thus illuminate the microRNA-221/PTEN axis may act as a promising strategy for the treatment of chemotherapy-resistant breast tumors.

SUBMITTER: Yin Y

PROVIDER: S-EPMC7013069 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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MicroRNA-221 promotes breast cancer resistance to adriamycin via modulation of PTEN/Akt/mTOR signaling.

Yin Yingchun Y Wang Xinmei X Li Tangyue T Ren Qi Q Li Liang L Sun Xiaoyu X Zhang Baohua B Wang Xinyun X Han Hongmei H He Yangyang Y Cao Zhen Z Sun Xiaojie X Zhou Ziqiang Z

Cancer medicine 20200103 4

As a prevalent tumor among women, breast cancer is still an incurable disease due to drug resistance. In this study, we report microRNA-221 to have a significant effect on breast cancer resistance to adriamycin. The microRNA-221 is elevated in tumor tissue compared with nearby nontumor samples, as well as in breast cancer cell line with adriamycin resistance (MCF-7/ADR) compared to its parental line (MCF-7) and the normal breast epithelial cell line (MCF-10A). Enforced level of microRNA-221 prom ...[more]

PMID: 31899608

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Project description:BackgroundMicroRNAs are short regulatory RNAs that negatively modulate protein expression at a post-transcriptional and/or translational level and are deeply involved in the pathogenesis of several types of cancers. Specifically, microRNA-221 (miR-221) is overexpressed in many human cancers, wherein accumulating evidence indicates that it functions as an oncogene. However, the function of miR-221 in human osteosarcoma has not been totally elucidated. In the present study, the effects of miR-221 on osteosarcoma and the possible mechanism by which miR-221 affected the survival, apoptosis, and cisplatin resistance of osteosarcoma were investigated.Methodology/principal findingsReal-time quantitative PCR analysis revealed miR-221 was significantly upregulated in osteosarcoma cell lines than in osteoblasts. Both human osteosarcoma cell lines SOSP-9607 and MG63 were transfected with miR-221 mimic or inhibitor to regulate miR-221 expression. The effects of miR-221 were then assessed by cell viability, cell cycle analysis, apoptosis assay, and cisplatin resistance assay. In both cells, upregulation of miR-221 induced cell survival and cisplatin resistance and reduced cell apoptosis. In addition, knockdown of miR-221 inhibited cell growth and cisplatin resistance and induced cell apoptosis. Potential target genes of miR-221 were predicted using bioinformatics. Moreover, luciferase reporter assay and western blot confirmed that PTEN was a direct target of miR-221. Furthermore, introduction of PTEN cDNA lacking 3'-UTR or PI3K inhibitor LY294002 abrogated miR-221-induced cisplatin resistance. Finally, both miR-221 and PTEN expression levels in osteosarcoma samples were examined by using real-time quantitative PCR and immunohistochemistry. High miR-221 expression level and inverse correlation between miR-221 and PTEN levels were revealed in osteosarcoma tissues.Conclusions/significanceThese results for the first time demonstrate that upregulation of miR-221 induces the malignant phenotype of human osteosarcoma whereas knockdown of miR-221 reverses this phenotype, suggesting that miR-221 could be a potential target for osteosarcoma treatment.

Dataset Information

MicroRNA-221 promotes breast cancer resistance to adriamycin via modulation of PTEN/Akt/mTOR signaling.

Publications

MicroRNA-221 promotes breast cancer resistance to adriamycin via modulation of PTEN/Akt/mTOR signaling.

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