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miR-4478 sensitizes ovarian cancer cells to irradiation by inhibiting Fus and attenuating autophagy.

ABSTRACT: Ovarian cancer (OC) is a type of cancer with high prevalence and shocking mortality in women around the world. Radioresistance is a major reason for OC relapse. Mounting studies have shown the significant function of dysregulated microRNAs (miRNAs) in cancer progression and the cellular response to irradiation. The present study inquired about the function and mechanism of microRNA (miR)-4478 in regulating radiosensitivity of OC cells. Results showed that miR-4478 was downregulated in OC, and a low miR-4478 level indicated a disappointing prognosis for OC patients. Besides, in OC cells exposed to irradiation, the expression of miR-4478 decreased over time. Functionally, the upregulation of miR-4478 retarded OC cell proliferation and sensitized OC cells to irradiation. Mechanistically, miR-4478 targeted and inhibited fused in sarcoma (Fus). Additionally, Fus was upregulated in OC and its expression further elevated in OC cells under irradiation. Furthermore, miR-4478 targeted Fus to inhibit autophagy, therefore sensitizing OC cells to irradiation. Collectively, our study uncovered miR-4478 as a novel radiosensitizer by targeting Fus in OC cells, which may shed a new light on developing targets for treating patients with OC, particularly those with radioresistance.

SUBMITTER: Wang L

PROVIDER: S-EPMC7901029 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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miR-4478 sensitizes ovarian cancer cells to irradiation by inhibiting Fus and attenuating autophagy.

Wang Lingling L Liu Ying Y Li Haixia H Zhang Cui C Wang Hongbo H Dai Shaochun S Cheng Wen W Sun Yan Y Zheng Xiulan X

Molecular therapy. Nucleic acids 20201203

Ovarian cancer (OC) is a type of cancer with high prevalence and shocking mortality in women around the world. Radioresistance is a major reason for OC relapse. Mounting studies have shown the significant function of dysregulated microRNAs (miRNAs) in cancer progression and the cellular response to irradiation. The present study inquired about the function and mechanism of microRNA (miR)-4478 in regulating radiosensitivity of OC cells. Results showed that miR-4478 was downre ...[more]

PMID: 33664992

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Project description:BackgroundOvarian cancer (OC) is the most lethal gynecological malignancy and the second leading cause of cancer-related death in women. Treatment with PARP inhibitors (PARPi), such as Olaparib, has been recently introduced for OC patients, but resistance may occur and underlying mechanisms are still poorly understood. The aim of this study is to identify target genes within the tumor cells that might cause resistance to Olaparib. We focused on Neuropilin 1 (NRP1), a transmembrane receptor expressed in OC and correlated with poor survival, which has been also proposed as a key molecule in OC multidrug resistance.MethodsUsing three OC cell lines (UWB, UWB-BRCA and SKOV3) as model systems, we evaluated the biological and molecular effects of Olaparib on OC cell growth, cell cycle, DNA damage and apoptosis/autophagy induction, through MTT and colony forming assays, flow cytometry, immunofluorescence and Western blot analyses. We evaluated NRP1 expression in OC specimens and cell lines by Western blot and qRT-PCR, and used RNA interference to selectively inhibit NRP1. To identify miR-200c as a regulator of NRP1, we used miRNA target prediction algorithms and Pearsons' correlation analysis in biopsies from OC patients. Then, we used a stable transfection approach to overexpress miR-200c in Olaparib-resistant cells.ResultsWe observed that NRP1 is expressed at high levels in resistant cells (SKOV3) and is upmodulated in partially sensitive cells (UWB-BRCA) upon prolonged Olaparib treatment, leading to poor drug response. Our results show that the selective inhibition of NRP1 is able to overcome Olaparib resistance in SKOV3 cells. Moreover, we demonstrated that miR-200c can target NRP1 in OC cells, causing its downmodulation, and that miR-200c overexpression is a valid approach to restore Olaparib sensitivity in OC resistant cells.ConclusionsThese data demonstrate that miR-200c significantly enhanced the anti-cancer efficacy of Olaparib in drug-resistant OC cells. Thus, the combination of Olaparib with miRNA-based therapy may represent a promising treatment for drug resistant OC, and our data may help in designing novel precision medicine trials for optimizing the clinical use of PARPi.

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miR-4478 sensitizes ovarian cancer cells to irradiation by inhibiting Fus and attenuating autophagy.

Publications

<i>miR-4478</i> sensitizes ovarian cancer cells to irradiation by inhibiting <i>Fus</i> and attenuating autophagy.

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