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MicroRNA-654-3p enhances cisplatin sensitivity by targeting QPRT and inhibiting the PI3K/AKT signaling pathway in ovarian cancer cells.

ABSTRACT: Dysregulation of microRNAs serves a crucial role in the chemosensitivity to cisplatin (DDP) in ovarian cancer (OVC). The abnormal expression of microRNA (miR)-654-3p has been reported in several types of human cancer. However, the association between miR-654-3p and cisplatin resistance in human OVC remains unclear. The present study aimed to investigate the role and mechanism of miR-654-3p in DDP resistance in OVC. The results demonstrated that miR-654-3p was significantly downregulated in ovarian cancer tissues and cells, as well as DDP-resistant IGROV-1/DDP cells, compared with adjacent non-tumoral tissue and IOSE386 cells. Overexpression of miR-654-3p significantly suppressed the proliferation and migration of ovarian cancer cells and increased the sensitivity of IGROV-1/DDP cells to DDP. Luciferase reporter assay demonstrated that quinolinate phosphoribosyl transferase (QPRT) was a target of miR-654-3p; overexpression of miR-654-3p inhibited QPRT expression by binding to the 3'-untranslated region of QPRT. In addition, inhibition of miR-654-3p reversed the suppressive effects of QPRT-targeting short interfering RNA on the proliferation and chemoresistance of ovarian cancer cells. Therefore, the results of the present study revealed a previously unrecognized regulatory mechanism that miR-654-3p enhances DDP sensitivity of OVC cells by downregulating QPRT expression; in addition, the present study highlighted the therapeutic implications of miR-654-3p upregulation in OVC.

SUBMITTER: Niu YC

PROVIDER: S-EPMC7388328 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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MicroRNA-654-3p enhances cisplatin sensitivity by targeting QPRT and inhibiting the PI3K/AKT signaling pathway in ovarian cancer cells.

Niu Yi-Chao YC Tong Jing J Shi Xiao-Fei XF Zhang Ting T

Experimental and therapeutic medicine 20200611 2

Dysregulation of microRNAs serves a crucial role in the chemosensitivity to cisplatin (DDP) in ovarian cancer (OVC). The abnormal expression of microRNA (miR)-654-3p has been reported in several types of human cancer. However, the association between miR-654-3p and cisplatin resistance in human OVC remains unclear. The present study aimed to investigate the role and mechanism of miR-654-3p in DDP resistance in OVC. The results demonstrated that miR-654-3p was significantly downregulated in ovari ...[more]

PMID: 32742380

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Project description:Background: Ovarian cancer is the most lethal female genital malignancy. Although cisplatin is the first-line chemotherapy to treat ovarian cancer patients along with debulking surgeries, its efficacy is limited due to the high incidence of cisplatin resistance. ATP citrate lyase (ACLY) has been shown to be a key metabolic enzyme and is associated with poor prognosis in various cancers, including ovarian cancer. Nevertheless, no studies have probed the mechanistic relationship between ACLY and cisplatin resistance. Methods: Survival analysis was mainly carried out online. Bioinformatic analysis was performed in R/R studio. Proliferative activity was measured by MTT and colony formation assays. Cell cycle and apoptosis analysis were performed by flow cytometry. The acquired-cisplatin-resistant cell line A2780/CDDP was generated by exposing A2780 to cisplatin at gradually elevated concentrations. MTT assay was used to calculate IC50 values of cisplatin. A xenograft tumor assay was used test cell proliferation in vivo. Results: Higher expression of ACLY was found in ovarian cancer tissue and related to poor prognosis. Knockdown of ACLY in A2780, SKOV3, and HEY cells inhibited cell proliferation, caused cell-cycle arrest by modulating the P16-CDK4-CCND1 pathway, and induced apoptosis probably by inhibiting p-AKT activity. Bioinformatic analysis of the GSE15709 dataset revealed upregulation of ACLY and activation of PI3K-AKT pathway in cells with acquired cisplatin resistance, in line with observations on A2780/CDDP cells that we generated. Knockdown of ACLY alleviated cisplatin resistance, and works synergistically with cisplatin treatment to induce apoptosis in A2780/CDDP cells by inhibiting the PI3K-AKT pathway and activating AMPK-ROS pathway. The ACLY-specific inhibitor SB-204990 showed the same effect. In A2780/CDDP cells, AKT overexpression could attenuate cisplatin re-sensitization caused by ACLY knockdown. Conclusions: Knockdown of ACLY attenuated cisplatin resistance by inhibiting the PI3K-AKT pathway and activating the AMPK-ROS pathway. These findings suggest that a combination of ACLY inhibition and cisplatin might be an effective strategy for overcoming cisplatin resistance in ovarian cancer.

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.

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MicroRNA-654-3p enhances cisplatin sensitivity by targeting QPRT and inhibiting the PI3K/AKT signaling pathway in ovarian cancer cells.

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MicroRNA-654-3p enhances cisplatin sensitivity by targeting QPRT and inhibiting the PI3K/AKT signaling pathway in ovarian cancer cells.

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