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Infectious Agents and Cancer

, 10:24

First Online: 27 July 2015Received: 06 March 2015Accepted: 02 July 2015DOI: 10.1186-s13027-015-0018-9

Cite this article as: Wang, Z., Wu, N., Tesfaye, A. et al. Infect Agents Cancer 2015 10: 24. doi:10.1186-s13027-015-0018-9

Abstract

Background and AimsHepatitis C virus HCV infection is a major risk factor for chronic hepatitis, cirrhosis and hepatocellular carcinoma HCC. Our aim is to explore molecular changes that underlie HCV infection-associated HCC in a humanized mouse model, in order to identify markers of HCC progression.

MethodsLiver proteins from human hepatocyte-engrafted and HCV-infected MUP-uPA-SCID-Bg mice were compared with either uninfected controls or HCV-infected but HCC-negative mice by Western blotting. MicroRNA markers of HCC positive or uninfected mouse liver were analyzed by RT-PCR.

ResultsWe describe the depletion of tumor suppressor proteins and induction of oncoproteins and oncogenic microRNAs oncomiRs in HCV-infection associated HCC. Similar depletion of PTEN protein in both HCC-positive and HCV-infected but HCC-negative liver suggests that PTEN depletion is an early, precancerous marker of HCC. By contrast, induction of oncoprotein cMyc, oncomiRs miR21, miR221 and miR141 and inflammatory response proteins correspond to HCC progression.

ConclusionsWhile the loss of PTEN is important for the initiation of HCV infection-associated HCC, PTEN depletion by itself is insufficient for tumor progression. Liver tumor progression requires induction of oncoproteins and oncomiRs. Overall, human hepatocyte-engrafted MUP-uPA-SCID-Bg mice provide a suitable small animal model for studying the effects of oncogenic changes that promote HCV infection associated HCC.

KeywordsHCV Infection-associated HCC AbbreviationsAktProtein Kinase B, a serine threonine-specific protein kinase that plays a key role in cell proliferation, transcription and migration

Alb-uPAAlbumin promoter driving urokinase plasminogen activator transgene

cMycProto-onco gene that codes for transcription factor named derived from Avian Myelocytoma viral oncogene

Cyclin D1Cell cycle kinase co-activator

DLC-1Deleted in Liver Cancer1 DLC1 gene encodes a GTPase activating protein that functions as a negative regulator of Rho family of GTPases

Haploinsufficiencywherein the retained functional copy of a gene is insufficient to maintain normal function

HBVHepatitis B virus

HCCHepatocellular carcinoma

HCVHepatitis C virus

IL-6RInterleukin 6 receptor

MUP-uPA-SCID-BgMajor Urinary Protein promoter driving urokinase plasminogen activator transgene in severe combined immune deficient mice, Bg strain

oncomiROncogenic microRNA

p5353kda tumor suppressor gene

PI3KPhosphatidylinositol-3-kinase

PTENPhosphatase and tensin homologue deleted on chromosome 10

RT-PCRReverse transcriptase-polymerase Chain Reaction

STAT3Signal transducer and activator of transcription protein 3 with inflammation-related oncogenic potential

WntOncogenic signaling proteins, described in mouse mammary tumor virus originally characterized from Drosophila Wingless g gene

β-CateninEncoded by CTNB1 gene in humans, a dual function protein regulating cell-cell adhesion and transcription overexpression of β-Catenin associated with many cancers including hepatocellular carcinoma

Zhao Wang and Ningbin Wu contributed equally to this work.

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Author: Zhao Wang - Ningbin Wu - Abeba Tesfaye - Stephen Feinstone - Ajit Kumar

Source: https://link.springer.com/




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