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

BACKGROUND/OBJECTIVE: IFNs 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). METHODS: H...

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Autores principales: Li, Wei, Huang, Xiaojie, Tong, Hongfei, Wang, Yuxuan, Zhang, Tong, Wang, Wen, Dai, Lili, Li, Tongzeng, Lin, Shengzhang, Wu, Hao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464253/
https://www.ncbi.nlm.nih.gov/pubmed/23056571
http://dx.doi.org/10.1371/journal.pone.0047040
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author Li, Wei
Huang, Xiaojie
Tong, Hongfei
Wang, Yuxuan
Zhang, Tong
Wang, Wen
Dai, Lili
Li, Tongzeng
Lin, Shengzhang
Wu, Hao
author_facet Li, Wei
Huang, Xiaojie
Tong, Hongfei
Wang, Yuxuan
Zhang, Tong
Wang, Wen
Dai, Lili
Li, Tongzeng
Lin, Shengzhang
Wu, Hao
author_sort Li, Wei
collection PubMed
description BACKGROUND/OBJECTIVE: IFNs 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). METHODS: HCC 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. RESULTS: Our 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). CONCLUSIONS: In 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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spelling pubmed-34642532012-10-10 Comparison of the Regulation of β-Catenin Signaling by Type I, Type II and Type III Interferons in Hepatocellular Carcinoma Cells Li, Wei Huang, Xiaojie Tong, Hongfei Wang, Yuxuan Zhang, Tong Wang, Wen Dai, Lili Li, Tongzeng Lin, Shengzhang Wu, Hao PLoS One Research Article BACKGROUND/OBJECTIVE: IFNs 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). METHODS: HCC 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. RESULTS: Our 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). CONCLUSIONS: In 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. Public Library of Science 2012-10-04 /pmc/articles/PMC3464253/ /pubmed/23056571 http://dx.doi.org/10.1371/journal.pone.0047040 Text en © 2012 Li et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Li, Wei
Huang, Xiaojie
Tong, Hongfei
Wang, Yuxuan
Zhang, Tong
Wang, Wen
Dai, Lili
Li, Tongzeng
Lin, Shengzhang
Wu, Hao
Comparison of the Regulation of β-Catenin Signaling by Type I, Type II and Type III Interferons in Hepatocellular Carcinoma Cells
title Comparison of the Regulation of β-Catenin Signaling by Type I, Type II and Type III Interferons in Hepatocellular Carcinoma Cells
title_full Comparison of the Regulation of β-Catenin Signaling by Type I, Type II and Type III Interferons in Hepatocellular Carcinoma Cells
title_fullStr Comparison of the Regulation of β-Catenin Signaling by Type I, Type II and Type III Interferons in Hepatocellular Carcinoma Cells
title_full_unstemmed Comparison of the Regulation of β-Catenin Signaling by Type I, Type II and Type III Interferons in Hepatocellular Carcinoma Cells
title_short Comparison of the Regulation of β-Catenin Signaling by Type I, Type II and Type III Interferons in Hepatocellular Carcinoma Cells
title_sort comparison of the regulation of β-catenin signaling by type i, type ii and type iii interferons in hepatocellular carcinoma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464253/
https://www.ncbi.nlm.nih.gov/pubmed/23056571
http://dx.doi.org/10.1371/journal.pone.0047040
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