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Exploring the Potential of Mesenchymal Stem Cell Sheet on The Development of Hepatocellular Carcinoma In Vivo
Published on: September 11, 2018
C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in
Shu-Guang Li1,2, Qian-Wei Shi1,3, Ling-Yan Yuan4
1Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China.
Background:
Triptolide 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.
Methods:
Cells 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.
Results:
Triptolide 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.
Conclusions:
The 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.
Insights
Triptolide effectively inhibits hepatocellular carcinoma (HCC) cell growth and triggers apoptosis by downregulating c-Myc and specific microRNA clusters. This study highlights triptolide as a promising agent for HCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triptolide, a diterpene triepoxide, exhibits potent antitumor properties.
- The precise mechanisms of triptolide's action in hepatocellular carcinoma (HCC) remain incompletely understood.
Purpose of the Study:
- To investigate the anti-HCC effects of triptolide.
- To elucidate the molecular mechanisms underlying triptolide's efficacy in HCC, focusing on microRNA regulation.
Main Methods:
- Cell proliferation and apoptosis assays (flow cytometry, western blot).
- In vivo efficacy assessment using HCC xenograft models.
- MicroRNA expression profiling (microarray, qRT-PCR) and functional studies (overexpression, knockdown).
- Chromatin immunoprecipitation assays to determine c-Myc binding to miR-106b-25.
Main Results:
- Triptolide suppressed HCC cell proliferation and induced apoptosis across various cell lines.
- Triptolide treatment led to significant tumor volume reduction in xenograft models.
- Triptolide downregulated miR-17-92 and miR-106b-25 clusters, upregulating targets BIM, PTEN, and p21.
- c-Myc-dependent suppression of these miRNAs by triptolide enhanced cell death, mediated via ERCC3 interaction.
Conclusions:
- Triptolide modulates the c-Myc/miRNA clusters/target gene axis, enhancing its antitumor activity in HCC.
- Triptolide demonstrates potential as a chemotherapeutic agent for hepatocellular carcinoma.
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