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The negative feedback between miR‐143 and DNMT3A regulates cisplatin resistance in ovarian cancer
Author(s) -
Han Xi,
Liu Dan,
Zhou Yuanyuan,
Wang Lijie,
Hou Huilian,
Chen He,
Zhang Lirui,
Chen Wei,
Li Xu,
Zhao Le
Publication year - 2021
Publication title -
cell biology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.932
H-Index - 77
eISSN - 1095-8355
pISSN - 1065-6995
DOI - 10.1002/cbin.11486
Subject(s) - cisplatin , downregulation and upregulation , ovarian cancer , methylation , chemistry , cancer research , cell culture , microbiology and biotechnology , cell growth , biology , cancer , gene , chemotherapy , biochemistry , genetics
Emerging evidence suggests that miR‐143 plays an important role in the regulation of tumor sensitivity to chemotherapeutic agents. The study explores the underlying mechanism of miR‐143 in reversing cisplatin resistance in ovarian cancer. The cisplatin‐resistant ovarian cancer cell line A2780/CDDP was induced and established via treating A2780 cells by gradually increasing cisplatin concentrations. The IC 50 values of A2780/CDDP and A2780 to cisplatin were 218.10 ± 1.12 and 21.99 ± 1.12 μM, respectively. Quantitative real‐time polymerase chain reaction (qRT‐PCR) results showed that miR‐143 was significantly decreased in A2780/CDDP cells compared with A2780 cells. miR‐143 overexpression decreased cisplatin resistance in A2780/CDDP, and miR‐143 inhibition decreased A2780 sensitivity to cisplatin. Results of qRT‐PCR, Western blot analysis, and luciferase reporter assay indicated that the direct target of miR‐143 was DNMT3A, which, in turn, was upregulated in A2780/CDDP. DNMT3A overexpression antagonized the sensitizing effect of miR‐143 on A2780/CDDP to cisplatin. Knocking down of DNMT3A reduced cisplatin resistance in A2780/CDDP, while overexpression of DNMT3A increased cisplatin resistance in A2780. Methylation‐specific polymerase chain reaction results showed that the methylation level in the promoter region of the miR‐143 precursor gene was higher in A2780/CDDP cells than in A2780 cells. DNMT3A mediated the hypermethylation of the miR‐143 precursor gene, resulting in miR‐143 downregulation in A2780/CDDP. miR‐143 inhibited cell growth of A2780/CDDP cell in nude mice. Our findings indicated the negative feedback between miR‐143 and DNMT3A as a crucial epigenetic modifier of cisplatin resistance in ovarian cancer.