Epithelial-mesenchymal transition expression profiles as a prognostic factor for disease-free survival in hepatocellular carcinoma: Clinical significance of transforming growth factor-β signaling

Mima, Kosuke; Hayashi, Hiromitsu; Kuroki, Hideyuki; Nakagawa, Shigeki; Okabe, Hidetoshi; Chikamoto, Akira; Watanabe, Masayuki; Beppu, Teruhiko; Baba, Hideo

doi:10.3892/ol.2012.954

Cited by 57 publications

(49 citation statements)

References 26 publications

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“…Loss of TGFβ responsiveness in tumour cells has substantial effects on tumour progression, not only through altered epithelial cell characteristics but also through gene expression changes that affect the tumour microenvironment. Activated TGFβ signalling has primarily been associated with an increase in metastasis and with poor patient prognosis, because EMT is induced 29,44 . However, abrogation of TGFβ signalling in carcinoma cells can also result in increased metastasis 45 .…”

Section: Disruption Of Tgfβ Signallingmentioning

confidence: 99%

The roles of TGFβ in the tumour microenvironment

2013

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Section: Disruption Of Tgfβ Signallingmentioning

confidence: 99%

The roles of TGFβ in the tumour microenvironment

2013

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“…In a recent analysis of a series of resected HCC specimens, a mesenchymal phenotype (high vimentin and low E-cadherin expression) was associated with shorter survival and enhanced TGF-β pathway activity (increased TGF-β1, phospho-SMAD-2, and phospho-β1 integrin expression)[58]. …”

Section: Role Of Tgf-β At the Cellular Levelmentioning

confidence: 99%

Perspectives of TGF-β inhibition in pancreatic and hepatocellular carcinomas

et al. 2013

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Advanced pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are non-curable diseases with a particularly poor prognosis. Over the last decade, research has increasingly focused on the microenvironment surrounding cancer cells, and its role in tumour development and progression. PDAC and HCC differ markedly regarding their pathological features: PDAC are typically stromal-predominant, desmoplastic, poorly vascularized tumours, whereas HCC are cellular and highly vascularized. Despite these very different settings, PDAC and HCC share transforming growth factor-β (TGF-β) as a common key-signalling mediator, involved in epithelial-to-mesenchymal transition, invasion, and stroma-tumour dialogue. Recently, novel drugs blocking the TGF-β pathway have entered clinical evaluation demonstrating activity in patients with advanced PDAC and HCC. TGF-β signalling is complex and mediates both pro- and anti-tumoural activities in cancer cells depending on their context, in space and time, and their microenvironment. In this review we provide a comprehensive overview of the role of the TGF-β pathway and its deregulation in PDAC and HCC development and progression at the cellular and microenvironment levels. We also summarize key preclinical and clinical data on the role of TGF-β as a target for therapeutic intervention in PDAC and HCC, and explore perspectives to optimize TGF-β inhibition therapy

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“…Furthermore, TGF-β has been shown to have a central role in the growth of hepatocytes [8]. With regard to the progression of HCC, it has previously been shown in HCC cell lines, such as Hep3B, HepG2, PLC/PRF5, that TGF-β signaling triggers EMT [9], characterized by lower E-cadherin expression and high vimentin expression in vitro [10].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-26b inhibits epithelial-mesenchymal transition in hepatocellular carcinoma by targeting USP9X

Shen

Lin²,

Yang

et al. 2014

BMC Cancer

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BackgroundMetastasis is responsible for the rapid recurrence and poor survival of malignancies. Epithelial-mesenchymal transition (EMT) has a critical role in metastasis. Increasing evidence indicates that EMT can be regulated by microRNAs (miRNAs). The aim of this study was to investigate the role of miR-26b in modulating epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC), as well as to identify its underlying mechanism of action.MethodsThe expression level of miR-26b was assessed in multiple HCC cell lines (HepG2, MHCC97H, Hep3B, MHCC97L, HCCC9810, BEL-7402, Huh7 and QGY-7703), as well as in liver tissue from patients with HCC. Follow-up studies examined the effects of a miR-26b mimic (increased expression) and a miR-26b inhibitor (decreased expression) on markers of EMT, wound healing and cell migration. The molecular target of miR-26b was also identified using a computer algorithm and confirmed experimentally.ResultsMiR-26b expression was decreased in HCC cell lines and was inversely correlated with the grade of HCC. Increased expression of miR-26b inhibited the migration and invasiveness of HCC cell lines, which was accompanied by decreased expression of the epithelial marker E-cadherin and increased expression of the mesenchymal marker vimentin, at both the mRNA and protein expression levels. A binding site for miR-26b was theoretically identified in the 3′UTR of USP9X. Further studies revealed that overexpression of miR-26b repressed the endogenous level of USP9X protein expression. Overexpression of miR-26b also repressed Smad4 expression, whereas its inhibition elevated Smad4 expression.ConclusionsTaken together, our results indicate that miR-26b were inhibited in HCC. In HCC cell lines, miR-26b targeted the 3′UTR of USP9X, which in turn affects EMT through Smad4 and the TGF-β signaling pathway. Our analysis of clinical HCC samples verifies that miR-26b also targets USP9X expression to inhibit the EMT of hepatocytes. Thus, miR-26b may have some effects on the EMT of HCC cells.

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Epithelial-mesenchymal transition expression profiles as a prognostic factor for disease-free survival in hepatocellular carcinoma: Clinical significance of transforming growth factor-β signaling

Cited by 57 publications

References 26 publications

The roles of TGFβ in the tumour microenvironment

The roles of TGFβ in the tumour microenvironment

Perspectives of TGF-β inhibition in pancreatic and hepatocellular carcinomas

MicroRNA-26b inhibits epithelial-mesenchymal transition in hepatocellular carcinoma by targeting USP9X

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