Interferon-α2b and transforming growth factor-β1 treatments on HCC cell lines: Are Wnt/β-catenin pathway and Smads signaling connected in hepatocellular carcinoma?

Ceballos, María Paula; Parody, Juan Pablo; Álvarez, María Clara; Ingaramo, Paola I.; Carnovale, Cristina E.; Carrillo, María C.

doi:10.1016/j.bcp.2011.08.001

Cited by 24 publications

(17 citation statements)

References 49 publications

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“…To gain mechanistic insights into these cooperative signals, we analyzed the effects of IFN -2b and TGF 1 on Wnt/ -catenin pathway and Smads intermediates in HepG2/C3A and Huh7 HCC cell lines. We could demonstrate that IFN -2b or TGF 1 stimulations not only decreased cellular proliferation but also increased apoptotic cell death [142]. The apoptotic and anti-proliferative effects of both cytokines separately have already been reported in HepG2 and Huh7 [143][144][145].…”

Section: Studies In Hcc Cell Linessupporting

confidence: 63%

Reactive Oxygen Species Act as Signaling Molecules in Liver Carcinogenesis

Carrillo¹,

Álvarez²,

Parody³

et al. 2012

Lipid Peroxidation

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Section: Studies In Hcc Cell Linessupporting

confidence: 63%

Reactive Oxygen Species Act as Signaling Molecules in Liver Carcinogenesis

Carrillo¹,

Álvarez²,

Parody³

et al. 2012

Lipid Peroxidation

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“…And in preneoplastic rat livers, in vivo IFNα2b treatment inhibits Wnt/β-catenin/TCF pathway and promotes programmed cell death possibly providing a link with FOXO (forkhead box containing protein class O) pathway [23]. Additional study shows that IFNα2b attenuated Wnt/β-catenin signal by decreasing β-catenin and Frizzled7 receptor proteins contents and the interaction of β-catenin with TCF4, in HCC cell lines [24]. It is clear that there is a cross-linked interaction between IFN and β-catenin signaling, but as to how and under which circumstances still remain unclear.…”

Section: Discussionmentioning

confidence: 84%

Comparison of the Regulation of β-Catenin Signaling by Type I, Type II and Type III Interferons in Hepatocellular Carcinoma Cells

Huang

Tong

et al. 2012

PLoS ONE

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Background/ObjectiveIFNs are a group of cytokines that possess potent antiviral and antitumor activities, while β-catenin pathway is a proliferative pathway involved in carcinogenesis. Interaction between these two pathways has not been well elaborated in hepatocellular carcinoma (HCC).MethodsHCC cell lines, HepG2 and Huh7, were used in this study. β-catenin protein levels and corresponding signaling activities were observed by flow cytometry and luciferase assay, respectively. Cell proliferation was quantified by counting viable cells under microscope, and apoptosis by TUNEL assay. DKK1 and GSK3β levels were determined by flow cytometry. Secreted DKK1 was tested by ELISA. FLUD, S3I and aDKK1 were used to inhibit STAT1, STAT3 and DKK1 activities, respectively.ResultsOur findings show that all three types of IFNs, IFNα, IFNγ and IFNλ, are capable of inhibiting β-catenin signaling activity in HepG2 and Huh7 cells, where IFNγ was the strongest (p<0.05). They expressed suppression of cellular proliferation and induced apoptosis. IFNγ expressed greater induction ability when compared to IFNα and IFNλ (p<0.05). All tested IFNs could induce DKK1 activation but not GSK3β in HepG2 and Huh7 cells. IFNs induced STAT1 and STAT3 activation but by using specific inhibitors, we found that only STAT3 is vital for IFN-induced DKK1 activation and apoptosis. In addition, DKK1 inhibitor blocked IFN-induced apoptosis. The pattern of STAT3 activation by different IFNs is found consistent with the levels of apoptosis with the corresponding IFNs (p<0.05).ConclusionsIn hepatocellular carcinoma, all three types of IFNs are found to induce apoptosis by inhibiting β-catenin signaling pathway via a STAT3- and DKK1-dependent pathway. This finding points to a cross-talk between different IFN types and β-catenin signaling pathways which might be carrying a biological effect not only on HCC, but also on processes where the two pathways bridge.

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“…Inappropriate regulation and activation of Wnt is associated with various disorders, including cancer [36]. Wnt/b-catenin is a frequently dysregulated pathway responsible for initiating and sustaining HCCs [37]. In the absence of Wnt receptor ligands, b-catenin is localized at the cell membrane in a complex with E-cadherin.…”

Section: Mir-148a Inhibits Metastasis Of Hccmentioning

confidence: 99%

“…Inside this complex, CK1 phosphorylates b-catenin at Ser 45 as a priming site, followed by phosphorylation of Thr 41, Ser 37, and Ser 33 residues by GSK-3b. Phosphorylated b-catenin is then recognized for ubiquitination and proteasomal degradation [37]. Wnt receptor complexes at the cell surface are composed of a seven transmembrane domain Frizzled protein and a singlepass transmembrane protein of the LDL receptorrelated protein family.…”

Section: Mir-148a Inhibits Metastasis Of Hccmentioning

confidence: 99%

Inhibitions of epithelial to mesenchymal transition and cancer stem cells‐like properties are involved in miR‐148a‐mediated anti‐metastasis of hepatocellular carcinoma

Yan

Dong

Zhong

et al. 2013

Molecular Carcinogenesis

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The epithelial-mesenchymal transition (EMT) and acquisition of cancer stem cells (CSCs)-like properties are essential steps in the metastasis and postsurgical recurrence of hepatocellular carcinomas (HCCs). The molecular mechanisms involved, however, remain obscure. As determined by an miRNA microarray analysis, there was lower expression of miR-148a in poorly differentiated HCC tissues relative to well-differentiated HCC tissues. MHCC97H and MHCC97L (HCC cells with migratory capacity) and HCC tissues with various differentiation status were selected for further investigation. The results showed that miR-148a levels inversely correlated with the differentiation status of HCC tissues. In MHCC97H and MHCC97L cells, over-expression of miR-148a blocked the EMT process, attenuated the expression of CD90 and CD44 (biomarkers for liver cancer stem cells), and inhibited their migratory capacity. Via TargetScan and microRNA.org algorithms, miR-148a was predicted to bind to the Wnt1 mRNA 3'-UTR. Wnt1 was confirmed as a target gene of miR-148a in HCC cells, and the Wnt signal pathway was determined to be involved in the miR-148a-mediated inhibition of EMT and CSCs-like properties of MHCC97H cells. Moreover, the expression of miR-148a in nonmetastatic HCC tissues was higher than that in metastatic HCC tissues. The results suggest that miR-148a inhibits the metastasis of HCCs by blocking EMT and CSCs-like properties through effects on the Wnt signaling pathway.

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Interferon-α2b and transforming growth factor-β1 treatments on HCC cell lines: Are Wnt/β-catenin pathway and Smads signaling connected in hepatocellular carcinoma?

Cited by 24 publications

References 49 publications

Reactive Oxygen Species Act as Signaling Molecules in Liver Carcinogenesis

Reactive Oxygen Species Act as Signaling Molecules in Liver Carcinogenesis

Comparison of the Regulation of β-Catenin Signaling by Type I, Type II and Type III Interferons in Hepatocellular Carcinoma Cells

Inhibitions of epithelial to mesenchymal transition and cancer stem cells‐like properties are involved in miR‐148a‐mediated anti‐metastasis of hepatocellular carcinoma

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