miRNA-708 functions as a tumour suppressor in hepatocellular carcinoma by targeting SMAD3

Li, Qi; Li, Sheng; Wu, Yaolu; Gao, Feng

doi:10.3892/ol.2017.6429

Cited by 33 publications

(24 citation statements)

References 44 publications

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“…The suppressive role of this signalling in cancers reflects in inhibition on tumour formation and inducement of growth arrest and apoptosis . On the other hand, TGF‐β/SMAD signalling shows the activity to promote tumour progression and metastasis, by inducing angiogenesis, inflammation and EMT . Yoshida and the colleagues have concluded, based on the reviews of the publications, that TGF‐β acts as a growth suppressor in normal epithelial cells after transient Ras activation.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of matrix metalloproteinase‐9 in breast cancer cell lines remarkably increases the cell malignancy largely via activation of transforming growth factor beta/SMAD signalling

et al. 2019

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Objectives: Matrix metalloproteinase 9 (MMP-9) has been frequently noticed in the breast cancers. In this study, we aim to investigate the associations of MMP-9 with the activation of transforming growth factor beta (TGF-β)/SMAD signalling and the malignancy of breast malignant tumour cells. Materials and methods:The distributions of MMP-9 and TGF-β in the tissues of canine breast cancers were screened by immunohistochemical assays. A recombinant plasmid expressing mouse MMP-9 was generated and transiently transfected into three different breast cancer cell lines. Cell Counting Kit-8 and colony formation assay were used to study cell viability. Migration and invasion ability were analysed by wound assay and transwell filters. Western blot and quantitative real-time PCR were used to determine the protein and mRNA expression.Result: Remarkable strong MMP-9 and TGF-β signals were observed in the malignant tissues of canine breast cancers. In the cultured three cell lines receiving recombinant plasmid expressing mouse MMP-9, the cell malignancy was markedly increased, including the cell colony formation, migration and epithelial-mesenchymal transition.The levels of activated TGF-β, as well as SMAD4, SMAD2/3 and phosphorylation of SMAD2, were increased, reflecting an activation of TGF-β/SMAD signalling. We also demonstrated that the inhibitors specific for MMP-9 and TGF-β sufficiently blocked the overexpressing MMP-9 induced the activation of SMAD signalling and enhancement on invasion in the tested breast cancer cell lines. Conclusion:Overexpression of MMP-9 increases the malignancy of breast cancer cell lines, largely via activation of the TGF-β/SMAD signalling.

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Section: Discussionmentioning

confidence: 99%

Overexpression of matrix metalloproteinase‐9 in breast cancer cell lines remarkably increases the cell malignancy largely via activation of transforming growth factor beta/SMAD signalling

et al. 2019

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“…Interestingly, the recovery of Smad3 signaling can restore the chemosensitivity of HCC cells [ 138 ]. Recently, several kinds of microRNAs (miRNA) have been reported to regulate Smad/EMT signaling; in contrast, miRNA-125b and miRNA-708 suppress Smad2 and Smad3 pathway and attenuate EMT [ 139 , 140 ], miRNA-520g down-regulates Smad7 and promotes EMT in HCC cells [ 141 ]. These data suggest that TGF-β/Smad-induced EMT signaling have important roles in the generation of highly invasive and chemoresistant cells with stem cell-like features in HCC.…”

Section: Emt In Liver Fibrosis and Hcc Progressionmentioning

confidence: 99%

Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis

Yoshida

Matsuzaki

Murata

et al. 2018

Cancers

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Chronic viral hepatitis is a global public health problem, with approximately 570 million persons chronically infected. Hepatitis B and C viruses increase the risk of morbidity and mortality from liver cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic complications that develop. Hepatitis virus infection induces transforming growth factor (TGF)-β, which influences microenvironments within the infected liver. TGF-β promotes liver fibrosis by up-regulating extracellular matrix production by hepatic stellate cells. TGF-β is also up-regulated in patients with HCC, in whom it contributes importantly to bringing about a favorable microenvironment for tumor growth. Thus, TGF-β is thought to be a major factor regulating liver fibrosis and carcinogenesis. Since TGF-β carries out regulatory signaling by influencing the phosphorylation of Smads, we have generated several kinds of phospho-specific antibodies to Smad2/3. Using these, we have identified three types of phospohorylated forms: COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C), linker phosphorylated Smad2/3 (pSmad2L and pSmad3L), and dually phosphorylated Smad3 (pSmad2L/C and pSmad3L/C). TGF-β-mediated pSmad2/3C signaling terminates cell proliferation; on the other hand, cytokine-induced pSmad3L signaling accelerates cell proliferation and promotes fibrogenesis. This review addresses TGF-β/Smad signal transduction in chronic liver injuries and carcinogenic processes. We also discuss the reversibility of Smad signaling after antiviral therapy.

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“…Over the past few decades, mounting studies have suggested that miRNAs can act as oncogenes or tumor suppressors in most types of cancer, including breast cancer [7], gastric cancer [8], prostate cancer [9] and colorectal cancer [10]. With regard to HCC, multiple previous studies have also demonstrated that miRNAs are involved in HCC progression [11–13]. However, only few reports regarding the roles of miRNAs in HBV-related HCC.…”

Section: Introductionmentioning

confidence: 99%

Identification of potential miRNA–mRNA regulatory network contributing to pathogenesis of HBV-related HCC

Lou

Liu²,

Ding

et al. 2019

J Transl Med

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BackgroundHepatitis B virus (HBV) is one of the major risk factors of hepatocellular carcinoma (HCC). Increasing evidence indicates that microRNA (miRNA)–mRNA axis is involved in HCC. However, a comprehensive miRNA–mRNA regulatory network in HBV-related HCC is still absent. This study aims to identify potential miRNA–mRNA regulatory pathways contributing to pathogenesis of HBV-related HCC.MethodsMicroarray GSE69580 was downloaded from Gene Expression Omnibus (GEO) database. GEO2R and ‘R-limma’ were used to conduct differential expression analysis. The common miRNAs appeared in the two analytic sets were screened as potential differentially expressed miRNAs (DE-miRNAs). The prognostic roles of screened DE-miRNAs in HCC were further evaluated using Kaplan–Meier plotter database. Target genes of DE-miRNAs were predicted by miRNet. Then, protein–protein interaction (PPI) networks were established for these targets via the STRING database, after which hub genes in the networks were identified by Cytoscape. Functional annotation and pathway enrichment analyses for the target genes were performed through DAVID database. Three enriched pathways related to HBV-related HCC were selected for further analysis and potential target genes commonly appeared in all three pathways were screened. Cytoscape was employed to construct miRNA-hub gene network. The expression and correlation of potential miRNAs and targets were further detected in clinical HBV-related HCC samples by qRT-PCR.Results7 upregulated and 9 downregulated DE-miRNAs were accessed. 5 of 7 upregulated DE-miRNAs and 5 of 7 downregulated DE-miRNAs indicated significant prognostic roles in HCC. 2312 and 1175 target genes were predicted for the upregulated and downregulated DE-miRNAs, respectively. TP53 was identified as the hub gene in the PPI networks. Pathway enrichment analysis suggested that these predicted targets were linked to hepatitis B, pathways in cancer, microRNAs in cancer and viral carcinogenesis. Further analysis of these pathways screened 20 and 16 target genes for upregulated and downregulated DE-miRNAs, respectively. By detecting the expression of 36 target genes, six candidate target genes were identified. Finally, a potential miRNA–mRNA regulatory network was established based on the results of qRT-PCR and expression correlation analysis.ConclusionsIn the study, potential miRNA–mRNA regulatory pathways were identified, exploring the underlying pathogenesis and effective therapy strategy of HBV-related HCC.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1761-7) contains supplementary material, which is available to authorized users.

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miRNA-708 functions as a tumour suppressor in hepatocellular carcinoma by targeting SMAD3

Cited by 33 publications

References 44 publications

Overexpression of matrix metalloproteinase‐9 in breast cancer cell lines remarkably increases the cell malignancy largely via activation of transforming growth factor beta/SMAD signalling

Overexpression of matrix metalloproteinase‐9 in breast cancer cell lines remarkably increases the cell malignancy largely via activation of transforming growth factor beta/SMAD signalling

Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis

Identification of potential miRNA–mRNA regulatory network contributing to pathogenesis of HBV-related HCC

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