Targeting blockage of STAT3 inhibits hepatitis B virus-related hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Yang Y
PROVIDER: S-EPMC4910934 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PURPOSE:MicroRNAs play key regulatory roles in the tumorigenesis of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). This study aimed to explore the regulatory effects of microRNA-98-5p (miR-98-5p) on the proliferation, migration, invasion, and apoptosis of HBV-HCC cells, as well as the underlying mechanisms involving nuclear factor-?B-inducing kinase (NIK). MATERIALS AND METHODS:The expressions of miR-98-5p and NIK in HBV-HCC tissues and cells, and the level of HBV DNA in HBV-HCC cells were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, migration, invasion, and apoptosis of HBV-HCC cells were analyzed by cell counting kit-8, wound healing, transwell, and flow cytometry assay, respectively. The targeting relationship between miR-98-5p and NIK was predicted by StarBase3.0 and verified by dual-luciferase reporter assay. HBV-HCC xenograft tumor model was constructed in mice to observe the tumor growth in vivo. RESULTS:The expression of miR-98-5p was declined in HBV-HCC tissues and cells. Overexpression of miR-98-5p markedly reduced the level of HBV DNA; inhibited the proliferation, migration, and invasion; and promoted the apoptosis of HBV-HCC cells. NIK was a target of miR-98-5p. Overexpression of miR-98-5p markedly decreased the protein expression of NIK in MHCC97H-HBV cells. NIK reversed the tumor-suppressing effect of miR-98-5p on HBV-HCC cells. Furthermore, overexpression of miR-98-5p significantly inhibited the xenograft tumor growth and decreased the expression of NIK in mice. CONCLUSION:MiR-98-5p inhibits the secretion of HBV, proliferation, migration, and invasion of HBV-HCC cells by targeting NIK.
| S-EPMC7256008 | biostudies-literature
Project description:Diol-type ginsenosides, such as protopanaxadiol (PPD), exhibit antioxidation, anti-inflammation, and antitumor effects. However, the antitumor effect of these ginsenosides and the mechanism of PPD remain unclear. In this work, the antitumor effects of several derivatives, including PPD, Rg5, Rg3, Rh2, and Rh3, were evaluated in five different cancer cell lines. PPD demonstrated the best inhibitory effects on the proliferation and migration of the five cancer cell lines, especially the hepatocellular carcinoma (HCC) cell lines. Therefore, the mechanism of action of PPD in HCC cells was elucidated. PPD inhibited the proliferation, migration, and invasion ability of HepG2 and PLC/PRF/5 cells in a dose-dependent manner. Western blot and immunofluorescence assay showed that PPD can alter the expression of epithelial-mesenchymal transition markers, increase E-cadherin expression, and decrease vimentin expression. Docking and biacore experiments revealed that STAT3 is the target protein of PPD, which formed hydrogen bonds with Gly583/Leu608/Tyr674 at the SH2 domain of STAT3. PPD inhibited the phosphorylation of STAT3 and its translocation from the cytosol to the nucleus, thereby inhibiting the expression of Twist1. PPD also inhibited tumor volume and tumor lung metastasis in PLC/PRF/5 xenograft model. In conclusion, PPD can inhibit the proliferation and metastasis of HCC cells through the STAT3/Twist1 pathway.
| S-EPMC6702205 | biostudies-literature
Project description:Approximately 350 million people worldwide are chronically infected by hepatitis B virus (HBV). HBV causes severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). In about 25% of affected patients, HBV infection proceeds to HCC. Therefore, the mechanisms by which HBV affects the host cell to promote viral replication and its pathogenesis have been the subject of intensive research efforts. Emerging evidence indicates that both autophagy and microRNAs (miRNAs) are involved in HBV replication and HBV-related hepatocarcinogenesis. In this review, we summarize how HBV induces autophagy, the role of autophagy in HBV infection, and HBV-related tumorigenesis. We further discuss the emerging roles of miRNAs in HBV infection and how HBV affects miRNAs biogenesis. The accumulating knowledge pertaining to autophagy and miRNAs in HBV replication and its pathogenesis may lead to the development of novel strategies against HBV infection and HBV-related HCC tumorigenesis.
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Project description:Alcohol consumption and chronic hepatitis B virus (HBV) infection are two well-established risk factors for Hepatocellular carcinoma (HCC); however, there remains a limited understanding of the molecular pathway behind the pathogenesis and progression behind HCC, and how alcohol promotes carcinogenesis in the context of HBV+ HCC. Using next-generation sequencing data from 130 HCC patients and 50 normal liver tissues, we identified a panel of microRNAs that are significantly dysregulated by alcohol consumption in HBV+ patients. In particular, two microRNAs, miR-944 and miR-223-3p, showed remarkable correlation with clinical indication and genomic alterations. We confirmed the dysregulation of these two microRNAs in liver cell lines treated by alcohol and acetaldehyde, and showed that manipulation of miR-223-3p and miR-944 expression induces significant changes in cellular proliferation, sensitivity to doxorubicin, and the expression of both direct-binding and downstream mRNA targets. Together, the results of this study suggest that alcohol consumption in HBV+ HCCs regulates microRNAs that likely play previously uncharacterized roles in the alcohol-associated carcinogenesis of HCC, and future studies of these microRNAs may be valuable for furthering the understanding and treatment of alcohol and HBV-associated HCC.
| S-EPMC5451132 | biostudies-literature
Project description:Chronic infections by hepatitis B virus (HBV) and hepatitis C virus (HCV) appear to be the most significant causes of hepatocellular carcinoma (HCC). Aberrant promoter methylation is known to be deeply involved in cancer, including HCC. In this study, we analyzed aberrant promoter methylation on genome-wide scale in 6 HCCs including 3 HBV-related and 3 HCV-related HCCs, 6 matched noncancerous liver tissues and 3 normal liver tissues by methylated DNA immunoprecipitation-on-chip analysis. Candidate genes with promoter methylation were detected more frequently in HCV-related HCC. Candidate genes methylated preferentially to HBV-related or HCV-related HCCs were detected and selected, and methylation levels of the selected genes were validated using 125 liver tissue samples, including 61 HCCs (28 HBV-related HCCs and 33 HCV-related HCCs) and matched 59 matched noncancerous livers, and 5 normal livers, by quantitative methylation analysis using MALDI-TOF mass spectrometry. Among analyzed genes, preferential methylation in HBV-related HCC was validated in 1 gene only. However, 15 genes were found methylated preferentially in HCV-related HCC, which was independent from age. Hierarchical clustering of HCC using these 15 genes stratified HCV-related HCC as a cluster of frequently methylated samples. The 15 genes included genes inhibitory to cancer-related signaling such as RAS/RAF/ERK and Wnt/b-catenin pathways. It was indicated that genes methylated preferentially in HCV-related HCC exist, and it was suggested that DNA methylation might play an important role in HCV-related HCC by silencing cancer-related pathway inhibitors. we analyzed aberrant promoter methylation in 6 HCC clinical samples (including 3 HBV-related HCCs and 3 HCV-related HCCs) and their matched noncancerous tissues on genome-wide scale by the method. Candidate regions of promoter methylation preferentially to HBV-related HCC and HCV-related HCC were selected, and the methylation levels of these genes were measured quantitatively using MALDI-TOF mass spectrometry. Expression levels of these 6 pairs of HCC and 4 more pairs of HCCs and surrounding noncancerous tissues were analyzed by expression array and are reported in this Series. <br><br>This experiment was reloaded in November 2010 after additional curation. this dataset is part of the TransQST collection.
2010-07-06 | E-GEOD-19665 | biostudies-arrayexpress
Project description:Chronic infections by hepatitis B virus (HBV) and hepatitis C virus (HCV) appear to be the most significant causes of hepatocellular carcinoma (HCC). Aberrant promoter methylation is known to be deeply involved in cancer, including HCC. In this study, we analyzed aberrant promoter methylation on genome-wide scale in 6 HCCs including 3 HBV-related and 3 HCV-related HCCs, 6 matched noncancerous liver tissues and 3 normal liver tissues by methylated DNA immunoprecipitation-on-chip analysis. Candidate genes with promoter methylation were detected more frequently in HCV-related HCC. Candidate genes methylated preferentially to HBV-related or HCV-related HCCs were detected and selected, and methylation levels of the selected genes were validated using 125 liver tissue samples, including 61 HCCs (28 HBV-related HCCs and 33 HCV-related HCCs) and matched 59 matched noncancerous livers, and 5 normal livers, by quantitative methylation analysis using MALDI-TOF mass spectrometry. Among analyzed genes, preferential methylation in HBV-related HCC was validated in 1 gene only. However, 15 genes were found methylated preferentially in HCV-related HCC, which was independent from age. Hierarchical clustering of HCC using these 15 genes stratified HCV-related HCC as a cluster of frequently methylated samples. The 15 genes included genes inhibitory to cancer-related signaling such as RAS/RAF/ERK and Wnt/b-catenin pathways. It was indicated that genes methylated preferentially in HCV-related HCC exist, and it was suggested that DNA methylation might play an important role in HCV-related HCC by silencing cancer-related pathway inhibitors.
2010-07-06 | GSE19665 | GEO
Project description: Not available
| S-DIXA-D-1053 | biostudies-other
Project description:Although partial hepatectomy (PH) to remove tumors provides a potential cure of hepatocellular carcinoma (HCC), long-term survival of hepatitis B virus (HBV)-related HCC patients after PH remains a big challenge. Early recurrence within 2 years post-PH is associated with the dissemination of primary HCC. However, late recurrence after 2 years post-PH is supposed due to the de novo or a secondary tumor. Since PH initiates liver regeneration (LR), we hypothesize that LR may accelerate tumorigenesis through activation of pre-existing precancerous lesions in the remaining liver. In this study, we explored the potential role of several LR-related factors in the de novo recurrence in a HBV X protein (HBx) transgenic mouse model receiving PH to mimic human HCC development. Following PH, we observed that tumor development was significantly accelerated from 16.9 to 10.4 months in HBx transgenic mice. The expression of suppressor of cytokine signaling (SOCS) family proteins was remarkably suppressed in livers of HBx transgenic relative to non-transgenic mice from early to late stages after PH as compared with non-PH mice. The expression of transforming growth factor-β (TGF-β)/Smad pathway, hepatocyte growth factor (HGF), Myc, signal transducer and activator of transcription 3 (STAT3), and β-Catenin also showed a significant difference between livers of HBx transgenic and non-transgenic mice at variable time points after PH in comparison with non-PH mice. Taken together, our results provide an explanation for the high de novo recurrence of HBV-related HCC after PH, probably through induction of the sequential changes of LR-related SOCS family proteins, growth factors, and transcription factors, which may promote growth on the precancerous remnant liver.
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Project description:Theaflavins, the major black tea polyphenols, have been reported to exhibit promising antitumor activities in several human cancers. However, the role of theaflavins in hepatocellular carcinoma (HCC) is still unknown. In this study, we found that theaflavins could significantly inhibit proliferation, migration, and invasion, and induce apoptosis in HCC cells in vitro. Furthermore, we found that theaflavins inhibited the growth and metastasis of HCC in an orthotopic model and a lung metastasis model. Immunohistochemical analyses and terminal deoxynucleotidyl transferase dUTP nick end-labeling assays showed that theaflavins could suppress proliferation and induce apoptosis in vivo. Theaflavins also suppressed constitutive and inducible signal transducer and activator of transcription 3 (STAT3) phosphorylation. The downstream proteins regulated by STAT3, including the antiapoptotic proteins (Bcl-2 and Survivin) and the invasion-related proteins (MMP-2, MMP-9), were also downregulated after theaflavins treatment. Theaflavins induced apoptosis by activating the caspase pathway. Together, our results suggest that theaflavins suppress the growth and metastasis of human HCC through the blockage of the STAT3 pathway, and thus may act as potential therapeutic agents for HCC.
| S-EPMC4951064 | biostudies-literature
Project description:Hepatitis C virus (HCV) is a leading etiology of hepatocellular carcinoma (HCC). The interaction of HCV with its human host is complex and multilayered; stemming in part from the fact that HCV is a RNA virus with no ability to integrate in the host's genome. Direct and indirect mechanisms of HCV-induced HCC include activation of multiple host pathways such as liver fibrogenic pathways, cellular and survival pathways, interaction with the immune and metabolic systems. Host factors also play a major role in HCV-induced HCC as evidenced by genomic studies identifying polymorphisms in immune, metabolic, and growth signaling systems associated with increased risk of HCC. Despite highly effective direct-acting antiviral agents, the morbidity and incidence of liver-related complications of HCV, including HCC, is likely to persist in the near future. Clinical markers to selectively identify HCV subjects at higher risk of developing HCC have been reported however they require further validation, especially in subjects who have experienced sustained virological response. Molecular biomarkers allowing further refinement of HCC risk are starting to be implemented in clinical platforms, allowing objective stratification of risk and leading to individualized therapy and surveillance for HCV individuals. Another role for molecular biomarker-based stratification could be enrichment of HCC chemoprevention clinical trials leading to smaller sample size, shorter trial duration, and reduced costs.
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