Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice†

Ghebranious, Nader; Sell, Stewart

doi:10.1002/hep.510270211

Cited by 74 publications

(62 citation statements)

References 36 publications

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“…No tumors of any grade were found in groups VB (7 males and 6 females) and VIB (7 males and 5 females), and only 18% of the male mice (2/11) and 0/7 females in VIIB (HBsAg positive, p53ϩ/ϩ) expressing the p53ser246 mutant had tumors and these were grade I. In addition, in the previously reported study 21 of the ''control'' groups, 2/8 male HBsAg transgenic, p53ϩ/Ϫ male mice not treated with AFB1 did have grade II tumors. Thus, although the data are not definitive, expression of the mutant appears only to have a significant effect in AFB1-treated mice.…”

Section: Detection Of Mutant P53 Protein Expressionmentioning

confidence: 51%

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The mouse equivalent of the human p53ser249 mutation p53ser246 enhances aflatoxin hepatocarcinogenesis in hepatitis B surface antigen transgenic and p53 heterozygous null mice

Ghebranious

Sell

1998

Hepatology

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The relative contribution to development of hepatocellular carcinoma of the mouse equivalent to the human p53ser249 mutation, found in human hepatocellular carcinoma associated with aflatoxin (AFB1) exposure, is compared with other major risk factors in a transgenic mouse model. Transgenic p53ser246 mice, expressing the mutant protein gene under the control of a truncated albumin promoter, were bred to mice lacking p53 (p53؊/؊) and to transgenic mice expressing hepatitis B surface antigen (HBsAg). AFB1 hepatocarcinogenesis was then determined in offspring with single or multiple risk factors by determination of the numbers of high-grade hepatic tumors at 13 months of age. In AFB1-treated male mice, expression of the p53ser246 mutation increases the incidence of high-grade tumors from 0% to 14% in HBsAg-negative, p53؉/؉ (wildtype homozygous) control mice; from 14% to 71% in HBsAg-negative, p53؉/؊ (wild-type heterozygous) mice; and from 62% to 100% in HBsAg-positive, p53؉/؉ mice. Thus, whereas HBsAg expression and AFB1 together are strongly cocarcinogenic, the presence of the p53ser246 mutant not only significantly enhances this cocarcinogenic effect, it also increases tumorigenesis in AFB1-treated p53 heterozygous and homozygous mice not expressing HBsAg. The possibility that the p53ser246 mutant protein may act as a promoting agent for AFB1 hepatocarcinogenesis is discussed. (HEPATOLOGY 1998;27:967-973.)The effect of the mouse equivalent to the human p53 mutation at position 249 resulting in an Arg to Ser mutation is examined in transgenic mouse models replicating the risk factors for development of hepatocellular carcinoma (HCC) in humans. The major cause of cancer mortality in subSaharan Africa and southern China is HCC. 1-3 Roughly two thirds of all cancer deaths in males and one third of cancer deaths in females in these areas are caused by HCC. [4][5][6][7] The high incidence of HCC is closely associated with liver injury caused by hepatitis B or C virus and consumption of food contaminated with aflatoxin (AFB1). 2,8,9 In the HCCs found in these high-risk areas a mutation in codon 249 of the p53 gene occurs with high frequency: 58% of HCCs from Qidong, China, and 53% from Mozambique. There is also a close association of the p53ser249 mutation in HCCs resulting from AFB1 exposure. 1,7 The objective of the work described in this paper is to determine, in transgenic mouse models, the contribution of the specific p53 mutation found in HCC in relationship to the other risk factors for human HCC. The p53ser246 mutation in the mouse corresponds to the p53ser249 mutation in humans. 10 The interaction of the major risk factors for human HCC and the effect of loss and specific mutation of p53 are examined in offspring of transgenic mice expressing the p53ser246 mutation bred to p53 null mice (p53ϩ/Ϫ) and to transgenic mice expressing hepatitis B surface antigen (HBsAg), with and without exposure to AFB1. These conditions duplicate in an animal model the major risk factors for, and the most frequent genetic change in,...

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Section: Detection Of Mutant P53 Protein Expressionmentioning

confidence: 51%

“…19,20 Because of the complexity of the data, the results of control groups of mice without the p53ser246 mutations are included in a separate report. 21 These are groups I to IV:…”

Section: Detection Of Mutant P53 Messenger Rna Using Reverse-transcrimentioning

confidence: 99%

The mouse equivalent of the human p53ser249 mutation p53ser246 enhances aflatoxin hepatocarcinogenesis in hepatitis B surface antigen transgenic and p53 heterozygous null mice

Ghebranious

Sell

1998

Hepatology

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“…Mouse liver tumors hardly contain any p53 mutations, even upon AFB 1 exposure, which led to the speculation that the nucleotide composition differences between mouse and human p53 genes could be one reason for the lack of mutations in mouse p53 in liver cancers. 29 However, the results presented here suggest that this may not be the case. Replacement of the whole DNA-binding domain in the mouse p53 locus with the human p53 counterpart in the Hupki mice has resulted in the generation of a valuable tool to study the mutagenic processes that occur in human cells upon exposure to carcinogens.…”

Section: Discussionmentioning

confidence: 54%

“…29 Further analysis using HBsAg transgenic mice demonstrated that although HBsAg and AFB 1 together were strongly carcinogenic, the presence of p53 mutation significantly enhanced the cocarcinogenic affect, thereby facilitating HCC formation. 29,37 These data raise the possibility that inactivation of p53 through mutations, such as found in AFB 1 -exposed individuals, may accelerate the adenoma to carcinoma transition. It is thus tempting to speculate that p53 mutations may be a late event that promotes carcinoma development in the liver.…”

Section: Discussionmentioning

confidence: 99%

Aflatoxin‐B exposure does not lead to p53 mutations but results in enhanced liver cancer of Hupki (human p53 knock‐in) mice

Tong

Lee

Galendo

et al. 2006

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is a common human malignancy that is often associated with risk factors such as aflatoxin-B 1 (AFB 1 ) exposure and Hepatitis-B virus infection in developing countries. There is a strong correlation between these risk factors and mutation of the tumor-suppressor gene p53 at codon 249. In vitro experiments have also shown that treatment of human liver cells with AFB 1 results in p53 mutations. A tumor-promoting role for mutant p53 was demonstrated using transgenic mice models, in which HCC development was accelerated upon AFB 1 -exposure. However, wild-type mice in which AFB 1 alone was used to induce liver cancers have failed to recapitulate p53 mutations, raising the possibility that mouse DNA context may not be appropriate for the generation of AFB 1 -induced p53 mutations. We have now tested this hypothesis using the Hupki mice (human p53 knock-in) in which the mouse DNA-binding domain has been replaced by the homologous human p53 segment. Mice were followed for 80 weeks after AFB 1 injection for survival and HCC formation. Hupki mice were found to be more susceptible to AFB 1 than wild-type mice. Moreover, only 19% of wild-type mice developed HCCs compared to 44% in Hupki mice. However, none of the liver tumors and normal tissues from Hupki mice contained any mutations in the DNAbinding domain of p53. These findings suggest that the human DNA context of the p53 gene alone may not be the sole determinant of AFB 1 -induced mutagenesis. Furthermore, humanized p53 appears not to be as effective as murine p53 in the mouse cellular environment in preventing malignant transformation. ' 2006 Wiley-Liss, Inc.Key words: aflatoxin-B 1 ; Hupki mice; hepatocellular carcinoma; liver cancer; p53; mutations Hepatocellular carcinoma (HCC) is a deadly disease, with poor prognosis and a 5-year survival of about 5%.1 It is one of the most common human malignancies in sub-Saharan Africa, South East Asia and China.2 Although the incidence of HCC is generally lower in developed countries such as USA, France, United Kingdom and Japan, it has increased significantly over the last decade.3-6 Several risk factors have been identified for HCC. It is believed that exposure to aflatoxin-B 1 (AFB 1 ) and Hepatitis-B virus (HBV) infection are the most common etiological risk factors associated with the high HCC incidence in developing countries.7 Besides these risk factors, epidemiological studies have suggested a strong relationship between AFB 1 exposure and a signature mutation on the tumor suppressor gene, p53. p53 is often mutated at codon 249 in HCCs arising from areas of high risk factors, resulting an amino acid change from arginine (AGG) to serine (AGT), which inactivates its function. 8 AFB 1 is a mycotoxin produced by Aspergillus flavus and related fungi that grows on crops including peanuts, corn and rice. 9 It is metabolized to exo-8,9-epoxide by cytochrome P450(s) and the metobolite reacts with the guanine residue to form AFB 1 -N7-Guanine adducts, resulting in a GC to TA transversion. 10 In vi...

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“…Nowadays, models based on the HBsAg transgenic mouse model of Chisari et al and the HBx transgenic mouse model of Kim et al [60] are commonly used to study mechanisms involved in hepatocarcinogenesis. These models are also applied to study possible synergistic relations between chemical carcinogens (such as aflatoxin B1 or diethyl nitrosamine) and HBV-infection [65][66][67] . Another application is the use of bitransgenic mouse models, in which mice are produced that are transgenic for a gene [48,68,69] .…”

Section: Hepatitis B Virus-associated Hccmentioning

confidence: 99%

Mouse models in liver cancer research: A review of current literature

Leenders¹,

Nijkamp²,

Rinkes³

2008

WJG

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Primary liver cancer remains one of the most lethal malignancies worldwide. Due to differences in prevalence of etiological factors the incidence of primary liver cancer varies among the world, with a peak in East-Asia. As this disease is still lethal in most of the cases, research has to be done to improve our understanding of the disease, offering insights for possible treatment options. For this purpose, animal models are widely used, especially mouse models. In this review, we describe the different types of mouse models used in liver cancer research, with emphasis on genetically engineered mice used in this field. We focus on hepatocellular carcinoma (HCC), as this is by far the most common type of primary liver cancer, accounting for 70%-85% of cases.

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Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice†

Cited by 74 publications

References 36 publications

The mouse equivalent of the human p53ser249 mutation p53ser246 enhances aflatoxin hepatocarcinogenesis in hepatitis B surface antigen transgenic and p53 heterozygous null mice

The mouse equivalent of the human p53ser249 mutation p53ser246 enhances aflatoxin hepatocarcinogenesis in hepatitis B surface antigen transgenic and p53 heterozygous null mice

Aflatoxin‐B exposure does not lead to p53 mutations but results in enhanced liver cancer of Hupki (human p53 knock‐in) mice

Mouse models in liver cancer research: A review of current literature

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