Abstract
Epithelial-mesenchymal transition (EMT) is one of the key mechanisms mediating cancer progression. MicroRNAs (miRs) are essential regulators of gene expression by suppressing translation or causing degradation of target mRNA. Growing evidence illustrates the crucial roles of miRs dysregulation in cancer development and progression. Here, we have found for the first time that the ginsenoside 20(S)-Rg3, a pharmacologically active component of Panax ginseng, potently increases miR-145 expression by downregulating methyltransferase DNMT3A to attenuate the hypermethylation of the promoter region in the miR-145 precursor gene. Restoration of DNMT3A reverses the inhibitory effect of 20(S)-Rg3 on EMT. FSCN1 is verified as the target of miR-145 to suppress EMT in human ovarian cancer cells. The results from nude mouse xenograft models further demonstrate the suppressive effect of miR-145 on malignant progression of ovarian cancer. Taken together, our results show that 20(S)-Rg3 blocks EMT by targeting DNMT3A/miR-145/FSCN1 pathway in ovarian cancer cells, highlighting the potentiality of 20(S)-Rg3 to be used as a therapeutic agent for ovarian cancer.
Highlights
Ovarian cancer is the most lethal gynecological tumor, existing predominantly in the form of epithelial ovarian cancer (EOC)[1, 2]
We have found for the first time that the ginsenoside 20(S)Rg3, a pharmacologically active component of Panax ginseng, potently increases miR-145 expression by downregulating methyltransferase DNMT3A to attenuate the hypermethylation of the promoter region in the miR-145 precursor gene
Our results show that 20(S)-Rg3 blocks Epithelial-mesenchymal transition (EMT) by targeting DNMT3A/miR-145/FSCN1 pathway in ovarian cancer cells, highlighting the potentiality of 20(S)-Rg3 to be used as a therapeutic agent for ovarian cancer
Summary
Ovarian cancer is the most lethal gynecological tumor, existing predominantly in the form of epithelial ovarian cancer (EOC)[1, 2]. DNMT3A and DNMT3B have been reported upregulated in ovarian cancers [26]. Both of them have been able to hypermethylate the promoter region in microRNA precursor genes and inversely regulate microRNA transcription. We discovered that 20(S)Rg3 enhanced miR-145 expression by downmodulating DNMT3A to attenuate the methylation level in the promoter region of miR-145 precursor gene. The promotion of miR145 by 20(S)-Rg3 directly targeted FSCN1 to reverse EMT in vitro and vivo. These results uncovered the novel anti-cancer mechanism of 20(S)-Rg3, and revealed the regulatory pathway for miR-145 expression
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