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MicroRNA‑34b expression enhances chemosensitivity of endometrial cancer cells to paclitaxel
Megumi Yanokura1, Kouji Banno1, Daisuke Aoki1
1Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo 160‑8582, Japan.
Abstract:
Aberrant DNA methylation is widely observed in various types of cancer, and expression of microRNAs (miRNAs/miRs) is suppressed by DNA methylation. The present study explored tumor suppressor miRNAs downregulated by DNA methylation in endometrial cancer cells, as the basis of a novel therapeutic approach for endometrial cancer. Among 821 candidate miRNAs, miR‑34b was identified as an upregulated miRNA after demethylation treatment in all four endometrial cancer cell lines (HEC‑108, SNG‑II, Ishikawa and HHUA) examined. miR‑34b expression with or without demethylation treatment in cancer cells was confirmed by TaqMan quantitative PCR. MYC and MET, the predicted target genes of miR‑34b, were downregulated at both the RNA and protein levels following miR‑34b overexpression. Following miR‑34b treatment, inhibition of cell growth and invasion, and cell cycle arrest were observed in HEC‑108 cells. Sensitivity to paclitaxel was increased in cancer cells with miR‑34b overexpression, compared with untreated cancer cells, but this difference was not identified for cisplatin or doxorubicin. In vivo, combination treatment with miR‑34b and paclitaxel markedly reduced tumor growth compared with treatment with negative control miRNA and paclitaxel. These data suggest that miR‑34b enhances paclitaxel sensitivity in endometrial cancer cells, and that miR‑34b and MET are key targets for treatment of endometrial cancer. The present results may contribute to the development of combination treatment with a demethylation agent, miR‑34b mimic or MET inhibitor and an anticancer drug.
Insights
Aberrant DNA methylation suppresses tumor suppressor microRNAs (miRNAs) in endometrial cancer. Restoring miR-34b expression via demethylation enhances paclitaxel sensitivity and inhibits tumor growth, offering a novel therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Aberrant DNA methylation is a hallmark of cancer, often silencing tumor suppressor genes, including microRNAs (miRNAs).
- Endometrial cancer exhibits altered DNA methylation patterns, impacting miRNA expression and potentially contributing to tumorigenesis.
Purpose of the Study:
- To identify tumor suppressor miRNAs downregulated by DNA methylation in endometrial cancer.
- To investigate the therapeutic potential of restoring miR-34b expression in endometrial cancer.
Main Methods:
- Screening of 821 candidate miRNAs for upregulation after demethylation treatment in endometrial cancer cell lines.
- Quantitative PCR to confirm miR-34b expression.
- Overexpression of miR-34b to assess effects on target genes (MYC, MET), cell growth, invasion, cell cycle, and chemosensitivity.
- In vivo studies combining miR-34b and paclitaxel treatment.
Main Results:
- miR-34b was identified as a significantly upregulated miRNA following demethylation across four endometrial cancer cell lines.
- miR-34b overexpression led to downregulation of its target genes, MYC and MET, and inhibited cell growth and invasion.
- miR-34b restoration increased sensitivity to paclitaxel in endometrial cancer cells.
- Combination therapy with miR-34b and paclitaxel markedly reduced tumor growth in vivo.
Conclusions:
- miR-34b functions as a tumor suppressor in endometrial cancer by targeting MYC and MET.
- Restoring miR-34b expression enhances paclitaxel sensitivity, suggesting a potential therapeutic strategy for endometrial cancer.
- miR-34b and MET are identified as key therapeutic targets for endometrial cancer treatment.
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