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Molecular Characterization of Hepatocarcinogenesis Using Mouse © 2015. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2015) 8, 743-753 doi:10.1242/dmm.017624 RESEARCH ARTICLE Molecular characterization of hepatocarcinogenesis using mouse models Wei Wei Teoh1, Min Xie1, Aadhitthya Vijayaraghavan2, Jadegoud Yaligar3, Wei Min Tong4, Liang Kee Goh2 and Kanaga Sabapathy1,2,5,* ABSTRACT INTRODUCTION Hepatocellular carcinoma (HCC) is a deadly disease, often unnoticed Hepatocellular carcinoma (HCC) is the second-most common until the late stages, when treatment options become limited. Thus, global cause of cancer death. It is endemic in Asia (Forner et al., there is a crucial need to identify biomarkers for early detection of 2012; Tsukuma et al., 2005) and is linked to multiple etiological developing HCC, as well as molecular pathways that would be factors, including diet, alcohol, hepatotoxins, inflammation and amenable to therapeutic intervention. Although analysis of human microorganisms (El-Serag, 2011). Although molecular advances HCC tissues and serum components may serve these purposes, over the last decade have led to an increased understanding of the inability of early detection also precludes possibilities of identification of genetic changes that occur in HCC, there is still inadequate biomarkers or pathways that are sequentially perturbed at earlier knowledge about the full spectrum of molecular pathways that are phases of disease progression. We have therefore explored the option deregulated during the course of hepatocarcinogenesis (Alves et al., of utilizing mouse modelsto understand in a systematic and longitudinal 2011; Minguez et al., 2009). This void is reflected in the dearth of manner the molecular pathways that are progressively deregulated by molecular pathways that are amenable for effective therapeutic various etiological factors in contributing to HCC formation, and we intervention, as well as the lack of biomarkers for early detection of report the initial findings in characterizing their validity. Hepatitis B HCC. surface antigen transgenic mice, which had been exposed to aflatoxin The majority of HCC patients in Asia harbor the hepatitis B virus (HBV) (South-east Asia, Taiwan and China) or the hepatitis C virus B1 at various stages in life, were used as a hepatitis model. Our findings confirm a synergistic effect of both these etiological factors, with a (HCV) (Japan and Korea) (Kao et al., 2000; Yuen et al., 2009). HBV gender bias towards males for HCC predisposition. Time-based and HCV carriers are at a higher risk of HCC than non-carriers, highlighting a crucial role for the hepatitis B and C viral components aflatoxin B1 treatment also demonstrated the requirement of non- quiescent liver for effective transformation. Tumors from these models in HCC formation (Kao et al., 2000). Epidemiological studies also with various etiologies resemble human HCCs histologically and at the suggest a strong relationship between factors such as alcohol molecular level. Extensive molecular characterization revealed the consumption, exposure to the fungal aflatoxin B1 (AFB1), high-fat presence of an 11-gene HCC-expression signature that was able to diet, microbes and other causes of cirrhosis, and HCC formation discern transformed human hepatocytes from primary cells, regardless (Berasain et al., 2009; Fagoonee et al., 2001; Hill-Baskin et al., 2009; of etiology, and from other cancer types. Moreover, distinct molecular Kew, 2003; Wild and Montesano, 2009). However, the detailed pathways appear to be deregulated by various etiological agents en knowledge of the effect of these environmental risk factors, either route to formation of HCCs, in which common pathways converge, alone or in combination, on the various molecular pathways they highlighting the existence of etiology-specific as well as common HCC- subvert in contributing to HCC development is poorly understood, specific molecular perturbations. This study therefore highlights the owing to the lack of systematic analysis of their roles in disease utility of these mouse models, which provide a rich resource for the progression. Moreover, it is still relatively unclear whether the various longitudinal analysis of molecular changes and biomarkers associated etiological factors eventually lead to a convergence of signaling with HCC that could be exploited further for therapeutic targeting. pathways, such that a common molecular HCC signature would emerge and could serve to differentiate HCCs from other cancers to KEY WORDS: Aflatoxin B1, Hepatitis B surface antigen, allow their effective targeting. Hepatocellular carcinoma, Mouse models Many animal models have been generated over the past two decades to model HCC. These include transgenic mice overexpressing factors such as TGFα and c-Myc, or viral factors, 1Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer such as HCV core protein, Hbx antigen and HB surface antigen Research, National Cancer Centre, 11 Hospital Drive, 169610, Singapore. 2Cancer (HBsAg) (Calvisi and Thorgeirsson, 2005; Chisari et al., 1985; and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Duke-NUS Graduate Medical School, 8 College Road, 169857, Singapore. 3Laboratory of Ghebranious and Sell, 1998; Moriya et al., 1998; Zhu et al., 2004). Molecular Imaging, Singapore Bioimaging Consortium, 11 Biopolis Way, Helios, Moreover, many chemically induced HCC models have also been 138667, Singapore. 4Institute of Basic Medical Sciences School of Basic Medicine, utilized to study the progression of the disease (Newell et al., 2008). Chinese Academy of Medical Sciences, Peking Union Medical College 5, Dong Dan San Tiao, Beijing 100005, China. 5Department of Biochemistry, National Some of these models resemble human HCCs and have contributed University of Singapore, 8 Medical Drive, 117597, Singapore. to varying degrees towards understanding the mechanisms and genes involved in HCC formation, highlighting the relevance of *Author for correspondence ([email protected]) such mouse models. However, many have failed to faithfully This is an Open Access article distributed under the terms of the Creative Commons Attribution recapitulate all pathological changes that occur when a normal License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. hepatocyte undergoes the transformation process to a malignant HCC with all the genetic changes that have been identified in human Received 25 July 2014; Accepted 17 April 2015 HCCs. Moreover, the few available, relevant models have not been Disease Models & Mechanisms 743 RESEARCH ARTICLE Disease Models & Mechanisms (2015) 8, 743-753 doi:10.1242/dmm.017624 these models to the human HCC context, and therefore promises to TRANSLATIONAL IMPACT provide useful insights in the future. Clinical issue Hepatocellular carcinoma (HCC) is the second-most common leading RESULTS global cause of cancer-related deaths. It is linked to multiple etiological Study design for longitudinal analysis of facts, including infection with hepatitis B virus (HBV) or hepatitis C virus hepatocarcinogenesis (HCV), a high-fat diet, alcohol consumption and exposure to We performed a systematic longitudinal analysis of molecular and hepatotoxins such as aflatoxin B1 (AFB1). HCC is a silent disease that physiological changes that occur during the process of HCC formation, is often only detected late when treatment options are limited. Late under conditions that mimic the absence or presence of hepatitis, or detection of HCC is primarily due to the lack of effective prognostic biomarkers. Although several animal models of HCC have been upon exposure to the hepatotoxin AFB1 at various stages in life. HBsAg generated over the past two decades, many fail to recapitulate all transgenic mice and their matched wild-type (WT) counterparts pathological changes that have been identified in human HCC. were treated with AFB1 on day 7 (D7) after birth, when the liver is Moreover, even the few available relevant models have not been at the proliferating stage (Shupe and Sell, 2004), or at adulthood at systematically interrogated to understand the progression of the disease 6 or 12 months of age (Fig. 1A). Efficacy of AFB1 injection to better or to identify biomarkers that could be used to detect HCC at an induce DNA adducts was confirmed by southwestern blotting using early stage. specific antibodies against the AFB1-formamidopyrimidine adducts Results (supplementary material Fig. S1). Approximately 15-25 mice per Here, the authors explore the possibility of utilizing mouse models to group were collected periodically at 3-month intervals, up until perform a systematic and longitudinal analysis of HCC development. 15 months, when all mice were finally sacrificed (Fig. 1A). A total of Specifically, the authors undertake a longitudinal histological and 727 mice, with about equal numbers of male and female mice, were molecular analysis of hepatocarcinogenesis regulated by HBV alone, used to determine the effect of gender on HCC formation AFB1 alone or both these etiological factors in combination, by treating (supplementary material Table S1A and B). transgenic mice expressing hepatitis B surface antigen (an established Livers and all other organs were collected, together with serum, model for human hepatitis) with AFB1. Tumors from animals treated with various etiologies resemble human HCCs histologically and at the from all animals at all
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