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Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition.
PLoS One 2009; 4(2):e4355Plos

Abstract

BACKGROUND

Chronic hepatitis C virus (HCV) infection and associated liver cirrhosis represent a major risk factor for hepatocellular carcinoma (HCC) development. TGF-beta is an important driver of liver fibrogenesis and cancer; however, its actual impact in human cancer progression is still poorly known. The aim of this study was to investigate the role of HCC-derived HCV core natural variants on cancer progression through their impact on TGF-beta signaling.

PRINCIPAL FINDINGS

We provide evidence that HCC-derived core protein expression in primary human or mouse hepatocyte alleviates TGF-beta responses in terms or growth inhibition or apoptosis. Instead, in these hepatocytes TGF-beta was still able to induce an epithelial to mesenchymal transition (EMT), a process that contributes to the promotion of cell invasion and metastasis. Moreover, we demonstrate that different thresholds of Smad3 activation dictate the TGF-beta responses in hepatic cells and that HCV core protein, by decreasing Smad3 activation, may switch TGF-beta growth inhibitory effects to tumor promoting responses.

CONCLUSION/SIGNIFICANCE

Our data illustrate the capacity of hepatocytes to develop EMT and plasticity under TGF-beta, emphasize the role of HCV core protein in the dynamic of these effects and provide evidence for a paradigm whereby a viral protein implicated in oncogenesis is capable to shift TGF-beta responses from cytostatic effects to EMT development.

Authors+Show Affiliations

Inserm, Unité 785, Villejuif, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19190755

Citation

Battaglia, Serena, et al. "Liver Cancer-derived Hepatitis C Virus Core Proteins Shift TGF-beta Responses From Tumor Suppression to Epithelial-mesenchymal Transition." PloS One, vol. 4, no. 2, 2009, pp. e4355.
Battaglia S, Benzoubir N, Nobilet S, et al. Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition. PLoS ONE. 2009;4(2):e4355.
Battaglia, S., Benzoubir, N., Nobilet, S., Charneau, P., Samuel, D., Zignego, A. L., ... Bourgeade, M. F. (2009). Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition. PloS One, 4(2), pp. e4355. doi:10.1371/journal.pone.0004355.
Battaglia S, et al. Liver Cancer-derived Hepatitis C Virus Core Proteins Shift TGF-beta Responses From Tumor Suppression to Epithelial-mesenchymal Transition. PLoS ONE. 2009;4(2):e4355. PubMed PMID: 19190755.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition. AU - Battaglia,Serena, AU - Benzoubir,Nassima, AU - Nobilet,Soizic, AU - Charneau,Pierre, AU - Samuel,Didier, AU - Zignego,Anna Linda, AU - Atfi,Azeddine, AU - Bréchot,Christian, AU - Bourgeade,Marie-Françoise, Y1 - 2009/02/03/ PY - 2008/07/22/received PY - 2008/12/18/accepted PY - 2009/2/5/entrez PY - 2009/2/5/pubmed PY - 2009/7/16/medline SP - e4355 EP - e4355 JF - PloS one JO - PLoS ONE VL - 4 IS - 2 N2 - BACKGROUND: Chronic hepatitis C virus (HCV) infection and associated liver cirrhosis represent a major risk factor for hepatocellular carcinoma (HCC) development. TGF-beta is an important driver of liver fibrogenesis and cancer; however, its actual impact in human cancer progression is still poorly known. The aim of this study was to investigate the role of HCC-derived HCV core natural variants on cancer progression through their impact on TGF-beta signaling. PRINCIPAL FINDINGS: We provide evidence that HCC-derived core protein expression in primary human or mouse hepatocyte alleviates TGF-beta responses in terms or growth inhibition or apoptosis. Instead, in these hepatocytes TGF-beta was still able to induce an epithelial to mesenchymal transition (EMT), a process that contributes to the promotion of cell invasion and metastasis. Moreover, we demonstrate that different thresholds of Smad3 activation dictate the TGF-beta responses in hepatic cells and that HCV core protein, by decreasing Smad3 activation, may switch TGF-beta growth inhibitory effects to tumor promoting responses. CONCLUSION/SIGNIFICANCE: Our data illustrate the capacity of hepatocytes to develop EMT and plasticity under TGF-beta, emphasize the role of HCV core protein in the dynamic of these effects and provide evidence for a paradigm whereby a viral protein implicated in oncogenesis is capable to shift TGF-beta responses from cytostatic effects to EMT development. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/19190755/Liver_cancer_derived_hepatitis_C_virus_core_proteins_shift_TGF_beta_responses_from_tumor_suppression_to_epithelial_mesenchymal_transition_ L2 - http://dx.plos.org/10.1371/journal.pone.0004355 DB - PRIME DP - Unbound Medicine ER -