C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells

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.

• Publication year

  2018

• Venue

  Journal of experimental & clinical cancer research : CR

• Publication date

  2018-03-09

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1186/s13046-018-0698-2PMID 29523159PMCID 5845216
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Triptolide inhibits viability and induces apoptosis in liver cancer cells through activation of the tumor suppressor gene p53.

  2017cited by this paper
• Triptolide inhibits tumor growth by induction of cellular senescence.

  2017cited by this paper
• Triptolide: structural modifications, structure-activity relationships, bioactivities, clinical development and mechanisms.

  2012cited by this paper
• MYC on the path to cancer.

  2012cited by this paper
• Microarray Analysis of Colorectal Cancer Stromal Tissue Reveals Upregulation of Two Oncogenic miRNA Clusters

  2012cited by this paper
• Circulating microRNA in digestive tract cancers.

  2012cited by this paper
• MicroRNAs in liver disease.

  2012cited by this paper
• Global cancer statistics

  2011cited by this paper
• XPB, a subunit of TFIIH, is a target of the natural product triptolide.

  2011cited by this paper
• Triptolide and its expanding multiple pharmacological functions.

  2011influential reference
• Effects of triptolide on RIZ1 expression, proliferation, and apoptosis in multiple myeloma U266 cells

  2010cited by this paper
• Increased accumulation of hypoxia-inducible factor-1α with reduced transcriptional activity mediates the antitumor effect of triptolide

  2010cited by this paper
• Targeting MYC-Regulated miRNAs to Combat Cancer.

  2010cited by this paper
• [Effects of triptolide-medicated serum on secretion function of adrenocortical cells isolated from rats].

  2010cited by this paper
• Causes and consequences of microRNA dysregulation in cancer

  2009cited by this paper
• c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism

  2009cited by this paper
• Triptolide is an inhibitor of RNA polymerase I and II–dependent transcription leading predominantly to down-regulation of short-lived mRNA

  2009cited by this paper
• MicroRNAs involved in tumor suppressor and oncogene pathways: Implications for hepatobiliary neoplasia

  2009cited by this paper
• Role of the miR‐106b‐25 microRNA cluster in hepatocellular carcinoma

  2009cited by this paper
• Emerging role of miR-106b-25/miR-17-92 clusters in the control of transforming growth factor beta signaling.

  2008cited by this paper
• Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.

  2008cited by this paper
• Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters.

  2008cited by this paper
• Elevated expression of the miR-17-92 polycistron and miR-21 in hepadnavirus-associated hepatocellular carcinoma contributes to the malignant phenotype.

  2008cited by this paper
• E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer.

  2008cited by this paper
• Direct regulation of the minichromosome maintenance complex by MYCN in neuroblastoma.

  2007cited by this paper
• The FUSE/FBP/FIR/TFIIH system is a molecular machine programming a pulse of c‐myc expression

  2006cited by this paper
• A microRNA expression signature of human solid tumors defines cancer gene targets

  2006cited by this paper
• Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a).

  2006cited by this paper
• Global Cancer Statistics, 2002

  2005cited by this paper
• Intensified Cloning Efforts Have Revealed Numer

  2004cited by this paper
• Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-κB activation in gastric cancer cells

  2001cited by this paper
• Vitronectin induces migration of activated T lymphocytes

  2000cited by this paper
• Hepatocellular carcinoma.

  2000cited by this paper
• N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation.

  2000cited by this paper
• The Myc oncoprotein: a critical evaluation of transactivation and target gene regulation

  1999cited by this paper
• The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.

  1993cited by this paper
• Differential expression of myc family genes during murine development

  1986cited by this paper
• Hepatocellular carcinoma.

  1986cited by this paper

• Anticancer activity and embolization evaluation of open porous PBVHx embolic microspheres loaded with triptolide.

  2026cites this paper
• Co-treatment with triptolide and RSL3 induces hepatocellular carcinoma cell apoptosis and ferroptosis

  2025cites this paper
• Harnessing the therapeutic potential of MicroRNAs and phytochemicals in modulating miRNA regulation during carcinogenesis.

  2025cites this paper
• Cytohesin-4/ARF6 facilitates the progression of acute myeloid leukemia through activating PIK3R5/PI3K/AKT pathway

  2025cites this paper
• The Malignant Transformation of Viral Hepatitis to Hepatocellular Carcinoma: Mechanisms and Interventions

  2025cites this paper
• PDCD11 Stabilizes C‐MYC Oncoprotein by Hindering C‐MYC‐SKP2 Negative Feedback Loop to Facilitate Progression of p53‐Mutant Breast and Colon Malignancies

  2025cites this paper
• Pharmacological, computational, and mechanistic insights into triptolide’s role in targeting drug-resistant cancers

  2025cites this paper
• Research Progress on Natural Products That Regulate miRNAs in the Treatment of Osteosarcoma

  2025cites this paper
• Histone Methyltransferase SETD1B Maintains Cancer Stem Cell Niche by Regulating the Crosstalk between CD24 and Surface Adhesion Molecules in Hepatocellular Carcinoma

  2025cites this paper
• Self-Amplified pH/ROS Dual-Responsive Co-Delivery Nano-System with Chemo-Photodynamic Combination Therapy in Hepatic Carcinoma Treatment

  2024cites this paper
• Bufonis venenum extract loaded novel cholesterol-free liposome for the treatment of hepatocellular carcinoma

  2024cites this paper
• Selective Antitumor Effect and Lower Toxicity of Mitochondrion-Targeting Derivatization of Triptolide.

  2024cites this paper
• Functions and targets of miRNAs in pharmacological and toxicological effects of major components of Tripterygium wilfordii Hook F

  2023cites this paper
• Friend or foe? The dual role of triptolide in the liver, kidney, and heart.

  2023cites this paper
• The role of microRNAs in hepatocellular carcinoma: Therapeutic targeting of tumor suppressor and oncogenic genes

  2023cites this paper
• Chemical synthesis of oligosaccharides and their application in new drug research.

  2023cites this paper
• Irf7 regulates the expression of Srg3 and ferroptosis axis aggravated sepsis-induced acute lung injury

  2023cites this paper
• Elucidating miRNA Function in Cancer Biology via the Molecular Genetics’ Toolbox

  2022cites this paper
• The miR-106b-25 cluster mediates drug resistance in myeloid leukaemias by inactivating multiple apoptotic genes

  2022cites this paper
• A systematic review of phytochemicals from Chinese herbal medicines for non-coding RNAs-mediated cancer prevention and treatment: From molecular mechanisms to potential clinical applications

  2022cites this paper
• OMICS Applications for Medicinal Plants in Gastrointestinal Cancers: Current Advancements and Future Perspectives

  2022cites this paper
• c-Myc Upregulated by High Glucose Inhibits HaCaT Differentiation by S100A6 Transcriptional Activation

  2021cites this paper
• Triptolide Attenuates Vascular Calcification by Upregulating Expression of miRNA-204

  2021cites this paper
• Natural products in the reprogramming of Cancer epigenetics.

  2021cites this paper
• MicroRNAs as crucial mediators in the pharmacological activities of triptolide (Review)

  2021influential citation
• Regulation of Non-coding RNAs in Cardiometabolic Tissues and Tumors

  2021cites this paper
• MiR-340 Promotes the Proliferation of Vascular Smooth Muscle Cells by Targeting von Hippel–Lindau Tumor Suppressor Gene

  2021cites this paper
• Triptolide: pharmacological spectrum, biosynthesis, chemical synthesis and derivatives

  2021cites this paper
• Toward the next-generation phyto-nanomedicines: cell-derived nanovesicles (CDNs) for natural product delivery.

  2021cites this paper
• The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

  2020cites this paper
• γ-Cyclodextrin metal–organic framework as a carrier to deliver triptolide for the treatment of hepatocellular carcinoma

  2020cites this paper
• Nanophytomedicine Based Novel Therapeutic Strategies in Liver Cancer

  2020cites this paper
• Cross-talk between oxidative stress signaling and microRNA regulatory systems in carcinogenesis: Focused on gastrointestinal cancers.

  2020cites this paper
• Participation of MicroRNAs in the Treatment of Cancer with Phytochemicals

  2020influential citation
• The Burden and Trends of Primary Liver Cancer Caused by Specific Etiologies from 1990 to 2017 at the Global, Regional, National, Age, and Sex Level Results from the Global Burden of Disease Study 2017

  2020cites this paper
• The Role of microRNAs in Organismal and Skin Aging

  2020cites this paper
• Low-dose triptolide enhances antitumor effect of JQ1 on acute myeloid leukemia through inhibiting RNA polymerase II in vitro and in vivo.

  2020cites this paper
• Galactosylated chitosan triptolide nanoparticles for overcoming hepatocellular carcinoma: Enhanced therapeutic efficacy, low toxicity, and validated network regulatory mechanisms.

  2019cites this paper
• RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 pathways and regulatory miRs as therapeutic targets in hepatocellular carcinoma

  2019cites this paper
• MicroRNA Networks Modulate Oxidative Stress in Cancer

  2019cites this paper
• Inhibition of RNA polymerase III transcription by Triptolide attenuates colorectal tumorigenesis

  2019cites this paper
• Triptolide exerts an anti-tumor effect on non‑small cell lung cancer cells by inhibiting activation of the IL‑6/STAT3 axis.

  2019cites this paper
• Bioactive Ingredients in Chinese Herbal Medicines That Target Non-coding RNAs: Promising New Choices for Disease Treatment

  2019cites this paper
• Traditional Chinese medicine-combination therapies utilizing nanotechnology-based targeted delivery systems: a new strategy for antitumor treatment

  2019cites this paper
• Global pathway view analysis of microRNA clusters in myasthenia gravis.

  2019cites this paper
• Cancer stem cells in hepatocellular carcinoma: an overview and promising therapeutic strategies

  2018cites this paper
• Recent advances in searching c-Myc transcriptional cofactors during tumorigenesis

  2018cites this paper
• The emerging roles of the polycistronic miR-106b∼25 cluster in cancer - A comprehensive review.

  2018cites this paper
• Circular RNA circC3P1 suppresses hepatocellular carcinoma growth and metastasis through miR-4641/PCK1 pathway.

  2018cites this paper