Abstract
BackgroundTriptolide is a structurally unique diterpene triepoxide with potent antitumor activity. However,the effect and mechanism of triptolide on hepatocellular carcinoma (HCC) is not well studied.MethodsCells were treated with triptolide, and the anti-HCC activity of triptolide was evaluated using flow cytometry, western blot, and xenograft studies. MicroRNA microarray and quantitative reverse-transcription polymerase chain reaction was used to identify differential microRNAs induced by triptolide. Chromatin immunoprecipitation assay was employed to study the interaction between c-Myc and genomic regions of miR106b-25. MicroRNAs overexpression and knockdown experiments were performed to determine the role of these microRNAs in triptolide-induced apoptosis.ResultsTriptolide inhibited cell proliferation and induced marked apoptosis in multiple HCC cell lines with different p53 status. Several signaling molecules involved in different pathways were altered after the treatment of triptolide. Xenograft tumor volume was significantly reduced in triptolide-treated group compared with vehicle control group. Two miRNA clusters, miR-17-92 and miR-106b-25, were significantly suppressed by triptolide, which resulted in the upregulation of their common target genes, including BIM, PTEN, and p21. In HCC samples, high levels of these miRNA clusters correlated with shorter recurrence free survival. Triptolide inhibited the expression of theses miRNAs in a c-Myc-dependent manner, which enhanced triptolide-induced cell death. We further showed that triptolide down-regulated the expression of c-Myc through targeting ERCC3, a newly identified triptolide-binding protein.ConclusionsThe triptolide-induced modulation of c-Myc/miRNA clusters/target genes axis enhances its potent antitumor activity, which indicates that triptolide serves as an attractive chemotherapeutic agent against HCC.
Highlights
Triptolide is a structurally unique diterpene triepoxide with potent antitumor activity
We further proved that both of the two miRNA clusters were directly transactivated by c-Myc, and triptolide down-regulated the expression of these miRNA clusters in a c-Myc dependent manner
Small interfering RNA and antisense oligonucleotides (ASOS) synthesis The siRNAs targeting MYC, E2F1, ERCC3 and control siRNA and the antisense oligonucleotides for miRNAs were synthesized by GenePharma (Shanghai, China)
Summary
Triptolide is a structurally unique diterpene triepoxide with potent antitumor activity. The effect and mechanism of triptolide on hepatocellular carcinoma (HCC) is not well studied. Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide with annual death exceeding 600,000 [1]. As key negative regulators in gene expression, miRNAs play an important role in many cellular processes, such as differentiation, proliferation, and apoptosis [5]. A large body of evidence has shown that miRNAs regulate molecular pathways in cancer by targeting various oncogenes and tumor suppressors, which play a vital role in cancer. Combinations of genomic analyses and functional studies have identified some miRNAs, such as miR-17-92, miR-21, and miR-221, which function as oncogenes in initiation and maintenance of HCC [7, 8]. Targeting oncogenic miRNAs and restoring tumor-suppressive miRNAs would be a reasonable therapeutic strategy for HCC patients
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