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    • microRNAs miRNAs of approximately nucleotides play vital rol

    2022-05-19

    microRNAs (miRNAs) of approximately 22 nucleotides play vital roles in cancer development and progression by regulating translational repression or decay of target messenger RNAs (mRNAs) through their binding to the 3′-untranslated regions (3′-UTRs) of target mRNAs with imprecise or precise complementarity [15,16]. Although a growing list of miRNAs have been reported as key regulators of cancer metabolism, the underlying mechanisms of action of miRNAs in cancer metabolism, with respect to the Warburg effect in particular, remain largely unknown [17]. Ginsenoside Rg3, one of the active ingredients in Panax ginseng, has been reported as a bioactive extract with anti-tumor effects [[18], [19], [20]]. On the basis of the orientation of the hydroxyl (OH) group on carbon-20, Rg3 is divided into two stereoisomers, 20(R)-Rg3 and 20(S)-Rg3 [21]. We previously found that 20(S)-Rg3, but not 20(R)-Rg3, potently blocked the Warburg effect and impaired proliferation and invasion of human ovarian cancer Rapalink-1 synthesis [22]. Deep sequencing showed that 20(S)-Rg3 altered miRNAs expression profile with miR-603 being one of the most-upregulated miRNAs. This report details the role and mechanism of miR-603 in the Warburg effect of ovarian cancer cells in vitro and in vivo.
    Materials and methods
    Results
    Discussion The glycolysis in the presence of oxygen, known as the Warburg effect, is a hallmark of rapidly proliferating cancer cells [[26], [27], [28]]. This unique metabolic pathway provides tumor cells with energy for ATP synthesis and substrates for macromolecular synthesis. Although the relationship between the Warburg effect and tumor progression or poor prognosis of cancer patients has been well established in various cancers including ovarian cancer [29,30], how the Warburg effect is regulated in cancer remains poorly understood. Knowledge gained from mechanistic studies can obviously aid the discovery of novel therapeutics for cancer treatment. HK2 is one of the key metabolic enzymes and highly expressed in cancer cells. Recent studies have demonstrated that HK2 is modulated by post-transcriptional regulations, including miRNAs [9]. We have previously found that 20(S)-Rg3 inhibits the Warburg effect in ovarian cancer cells, with several miRNAs upregulated by 20(S)-Rg3 [25]. However, the molecular mechanisms by which 20(S)-Rg3-upregulated miRNAs suppress the Warburg effect remain to be elucidated. Our results from miRNA deep sequencing and qRT-PCR verification assays showed that miR-603 was upregulated by 20(S)-Rg3. We further demonstrated that miR-603 was an anti-Warburg effect miRNA targeting HK2. So far, several miRNAs have been proposed as HK2 suppressors, including miR-143, miR-199a-5p, miR-145 [9,31,32] and the newly identified miR-532-3p [25]. Our work identified miR-603 as a new member of this anti-Warburg effect miRNA family. Whereas miR-603 acted as a tumor suppressor in triple-negative breast cancer [33] and thyroid cancer [34], it enhanced tumor growth in osteosarcoma cell lines [35] and glioma cell growth [36]. Our finding that miR-603 inhibited the Warburg effect and, consequently, the proliferation and invasion of ovarian cancer cells in vitro and in vivo supports the role of miR-603 as a tumor suppressor during ovarian cancer development. DNA hypermethylation is associated with the aberrant expression pattern of miRNAs [37,38]. To understand how miR-603 is modulated, we explored the involvement of DNA methylation in modulating the miRNA level based on our previous findings that 20(S)-Rg3 downregulated DNMT3A expression [25] and that the promoter of miR-603 precursor gene contained CpG islands. The negative regulation of DNA methylation on miR-603 was verified by the following observations. First, DNA methylation inhibitor 5-Aza decreased the methylation level in the promoter region of miR-603 precursor gene, and upregulated miR-603. Second, overexpression of DNMT3A increased the methylation level in the promoter region of miR-603 precursor gene, and downregulated miR-603. Third, 20(S)-Rg3 elevated miR-603 level via antagonizing DNMT3A-mediated DNA methylation in the miR-603 precursor gene promoter. DNMT3A, a member of the mammalian DNA methyltransferase family, was highly expressed in high-grade serous carcinoma and significantly associated with poor prognosis of patients [39]. The mechanism that 20(S)-Rg3 specifically reduced DNMT3A protein level rather than other DNA methyltransferases remained unknown. Since 20(S)-Rg3 had little effect on DNMT3A RNA level, a post-translational regulation mechanism is likely responsible for the downregulation of DNMT3A by 20(S)-Rg3.