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MircroRNA-139 sensitizes ovarian cancer cell to cisplatin-based chemotherapy through regulation of ATP7A/B

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Abstract

Purpose

Ovarian cancer remains a most malignant female cancer nowadays. The acquisition of chemoresistance to common-used cisplatin-based chemotherapy results in a decreased overall patient survival. The present study is aimed to investigate the role and mechanism by which miR-139/ ATPases7A/B axis modulates the chemoresistance of ovarian cancer to cisplatin-based chemotherapy.

Methods

The expression of miR-139 in cisplatin-sensitive (n = 23) and cisplatin-resistant (n = 14) ovarian cancer tissues and cell lines (CAOV-3 and SNU119) was determined using real-time PCR assays; its effect on ovarian cancer cell chemoresistance to different concentrations of cisplatin was then assessed by measuring the cell viability using MTT assays. Next, miR-139 binding to the 3′UTR of ATP7A/B was confirmed using luciferase reporter gene assays. Finally, the combined effect of miR-139 and ATP7A/B on the chemoresistance of ovarian cancer cell was assessed.

Results

miR-139 expression was down-regulated in cisplatin-resistant ovarian cancer tissues (**P < 0.01) and reduced by cisplatin treatment in ovarian cell lines (*P < 0.05, **P < 0.01); miR-139 could enhance cisplatin-induced suppression on ovarian cancer cell viability, shown as reduced lC50 values; ATP7A and ATP7B protein levesincreased approximately 2 ~ fold-changein cisplatin-resistant cell lines. MiR-139 directly bound to the 3′UTR of ATP7A/B, respectively; miR-139 inhibition increased lC50 values whereas ATP7A/B knockdown reduced lC50 values of CAOV-3 and SNU119 cell lines under cisplatin treatment; the effect of miR-139 inhibition could be partially attenuated by ATP7A/B knockdown.

Conclusions

MiR-139/ATP7A/B axis can be a reliable biomarker for ovarian cancer diagnosis, and may affect the chemoresistance of ovarian cancer to cisplatin-based chemotherapy; rescuing miR-139 expression thus to inhibit ATP7A/B might contribute to dealing with the chemoresistance of ovarian cancer.

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, The Third Xiangya Hospital of Central South University, No. 138, Tong zi po Rd, Yuelu District, Changsha, 410013, China

    Fang Xiao, Yueran Li, Yajun Wan & Min Xue

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  1. Fang Xiao
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  2. Yueran Li
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Contributions

Fang Xiao designed and performed the experiments, wrote the manuscript. Fang Xiao and Yueran Li have contributed to experimental work and data analysis. Yajun Wan and Min Xue conducted the experiments and revised the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Yajun Wan or Min Xue.

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Conflict of interest

Author Fang Xiao declares that she has no conflict of interest. Author Yueran Li declares that she has no conflict of interest. Author Yajun Wan declares that she has no conflict of interest. Author Min Xue declares that she has no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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280_2018_3548_MOESM1_ESM.tif

Fig. S1 Transfection efficiency and expression level confirmation (A-B) miR-139 mimics was transfected into CAOV3 and SNU119 cells to achieve ectopic miR-139 expression, as verified using real-time PCR assays. (C) The expression of ATP7A in CAOV3, SNU119, CAOV3/cDDP and SNU119/cDDP cells was determined by Immunoblotting. (D) The expression of miR-139 in CAOV3, SNU119, CAOV3/cDDP and SNU119/cDDP cells was determined by RT-PCR. (E) CAOV3 and SNU119 cells were transfected with miR-139 inhibitor to achieve miR-139 inhibition, as verified using real-time PCR assays. (F) The expression of ATP7B in CAOV3, SNU119, CAOV3/cDDP and SNU119/cDDP cells was determined by Immunoblotting. (TIF 773 KB)

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Xiao, F., Li, Y., Wan, Y. et al. MircroRNA-139 sensitizes ovarian cancer cell to cisplatin-based chemotherapy through regulation of ATP7A/B. Cancer Chemother Pharmacol 81, 935–947 (2018). https://doi.org/10.1007/s00280-018-3548-1

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