|
Sign In to gain access to subscriptions and/or personal tools.
|
Overview of the Molecular Biology of Hepatocellular Neoplasms and Hepatoblastomas of the Mouse Liver
Yongbaek Kim1,
Robert C. Sills1 and
Chris D. Houle2
1 Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA
2 Experimental Pathology Laboratories Inc., Research Triangle Park, North Carolina 27709, USA
Correspondence: Address correspondence to: Robert C. Sills, Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, MD B3-06, 111 Alexander Drive, Research Triangle Park, North Carolina 27709, USA; e-mail:sills{at}niehs.nih.gov
 |
Abstract
|
|---|
The molecular pathogenesis of chemically induced hepatocellular neoplasms and hepatoblastomas in the B6C3F1 mouse is unclear but may involve alterations in the β-catenin/Wnt signaling pathway as was recently described for human liver neoplasms. The objectives of this research were to characterize the mutation frequency and spectrum of β-catenin mutations and the intracellular localization of β-catenin protein accumulation in chemically induced hepatoblastomas and hepatocellular neoplasms. In the majority of the hepatoblastomas examined by immunohistochemical methods, both nuclear and cytoplasmic localization of β-catenin protein were detected, whereas in hepatocellular adenomas and carcinomas and normal liver only membrane staining was observed. Genomic DNA was isolated from paraffin sections of each liver tumor. β-catenin exon 2 (corresponds to exon 3 in humans) genetic alterations were identified in the majority of hepatoblastomas from exposed mice. Deletion mutations were identified more frequently than point mutations in hepatoblastomas. Hepatocellular adenomas and carcinomas from treated mice had mutations in exon 2 of the β-catenin gene which ranged from 32–43%, while 10% β-catenin mutations were detected in spontaneous neoplasms. By immunohistochemical methods cyclin D1 was observed in most nuclei of hepatoblastomas and strong expression of cyclin D1 was confirmed by Western analysis regardless of treatment. The cumulative data suggests that β-catenin mutations with upregulation of the β-catenin protein and Wnt signaling most likely increased cyclin D1 expression. Cyclin D1 may provide an advantage during tumor progression of hepatocellular neoplasms and hepatoblastomas. The review will also focus on other genes which are important in mouse and human liver tumors.
Key Words: Mouse • hepatocellular carcinoma • hepatocellular adenoma • hepatoblastoma • liver • hepatocarcinogenesis
|
Hepatocellular Neoplasms
|
|---|
Human hepatocellular carcinoma (HCC) accounts for more than 90% of all primary liver cancer. High rates of liver cancer incidence are reported in large portions of Asia and Africa (Mathers et al., 2002) and affects men more frequently than women (Parkin et al., 1999). In mice, hepatocellular adenoma is the most common spontaneous liver neoplasm, followed by HCC. Similar to the human tumors, hepatocellular adenomas and HCC in the mouse occur more frequently in males than females (Harada et al., 1999).
The etiology of human HCC is multifactorial and include exposure to naturally occurring carcinogens, viral infection of hepatitis B virus (HBV) and hepatitis C virus (HCV), genetic disease, industrial chemicals, pharmacologic agents, various pollutants, and lifestyle factors (Coleman, 2003). Transgenic mice expressing HBV X protein are more susceptible to carcinogen induced hepatocarcinogenesis (Zhu et al., 2004). Chronic hepatitis and cirrhosis also represent significant risk factors for liver cancer. Regenerative hepatocytes in the inflamed liver give rise to hyperplastic hepatocyte nodules, and these further progress to dysplastic nodules, which may progress to hepatocellular adenomas or carcinomas (Coleman, 2003). Different genes have been implicated in hepatocarcinogenesis including genes regulating DNA damage responses, genes involved in cell cycle control, genes involved in growth inhibition and apoptosis, and genes responsible for cell-cell interaction and signal transduction (Coleman, 2003).
Proliferative preneoplastic hepatocellular lesions have increased expression of growth factors and their receptors such as transforming growth factor  (TGF-), insulin-like growth factor II (IGF II), hepatocyte growth factor (HGF), and c-met (Coleman, 2003). The cognate receptors and growth factors may be produced in an autocrine manner or through paracrine signaling pathways. Mouse models including TGF- transgenic mice, c-myc/TGF- double transgenic mice and c-myc-HGF double transgenic mice demonstrated an increased incidence of liver tumors (Fausto, 1999). One-third of the TGF transgenic mice had elevated c-myc levels; furthermore, 75% of these tumors had elevated levels of IGF II mRNA, suggesting that TGF and IGF II genes contribute to the formation of liver tumors. In mice, a genotoxic hepatocarcinogen, diethyl-nitrosamine (DEN), induced re-expression of IGF II during the early stages of liver carcinogenesis (Lahm et al., 2002).
The major molecular features of human HCC include aneuploidy and chromosomal aberrations, activation of protooncogenes, and inactivation of tumor suppressor genes. About 40% of HCC exhibit an aneuploid DNA content and numerical chromosomal abnormalities (Mise et al., 1998). The chromosomal regions most frequently involved in structural rearrangements are on chromosomes 1, 7, and 8 (Parada et al., 1998). DNA hypomethylation on pericentromeric satellite regions has been shown to significantly correlate with the loss of functional DNA methyltransferase activity and is also associated with chromosomal instability in precancerous conditions as well as HCC (Saito et al., 2002). Some HCC exhibit microsatellite instability associated with a loss of heterozygosity in mismatch repair genes (including hMSH2 and hMLH1) (Macdonald et al., 1998).
Increased levels of expression of c-H-ras, c-N-ras, and c-K-ras have been reported in HCC, as well as some pre-neoplastic lesions in humans (Coleman, 2003). The overexpression of the p21 ras protein in nearly all HCC examined suggests that the ras-MAPK pathway is hyperactive in these neoplasms (Huynh, 2004). K-ras mutations were found in 5 of 12 (42%) HCC in workers exposed to vinyl chloride (Weihrauch et al., 2001). H-ras mutations, which are often found in spontaneous mouse liver tumors, were not observed in the diethanolamine (DEA)-induced tumors suggesting that these tumors may develop by pathways which are independent of ras signal transduction (Hayashi et al., 2003). Then, 38 of 50 methylene chloride-induced liver tumors had mutations in H-ras codon 61 (Devereux et al., 1993), indicating that the H-ras signaling pathway plays a major role in development of liver tumors induced by this chemical.
Mutations of the p53 gene occur in conjunction with loss of heterozygosity of the p53 locus in human HCC, with most mutations occurring within the highly conserved DNA binding region of the gene including exons 5–9 (Hainaut et al., 1998). Point mutations in codon 249 of the p53 gene accounted for approximately 30% of p53 mutations in human HCC (Coleman, 2003). G to T transversions at codon 249 (AGG to AGT, arginine to serine) of the p53 gene have been attributed to aflatoxin B1 exposure (Puisieux et al., 1991). Preneoplastic liver nodules in rats treated with aflatoxin B1 showed no alterations in p53 expression or mutations in exons 5–8 of the p53 gene, suggesting that p53 mutations are not an early event in AFB1-induced hepatocarcinogenesis (Liu et al., 1996). A higher percentage of p53 genetic alterations have been detected in advanced stages of HCC (Hsu et al., 1993), suggesting that p53 abnormalities may be associated with tumor progression in humans.
β-catenin mutations in human HCC have been frequently reported (Nhieu et al., 1999; Yamamoto et al., 2003). β-catenin mutations were detected more frequently in HCV-related HCC (45.8%) than in HBV-related HCC (22.2%) (Yamamoto et al., 2003). Some studies suggest there may be a chemical specific involvement of β-catenin activation in mouse liver tumors and that these alterations may be early events in mouse hepatocellular carcinogenesis (Devereux et al., 1999). Eleven of 34 (32%) hepatocellular adenomas and carcinomas from diethanolamine (DEA) treated B6C3F1 mice had mutations in exon 2 of the β-catenin gene and all tumors exhibited mild to moderate membrane staining of β-catenin protein (Hayashi et al., 2003). Similarly, 80% of neoplasms from mice treated with DEN (initiator) and phenobarbital had Catnb (β-catenin) mutations, whereas H-ras mutations were not found (Aydinlik et al., 2001). In contrast, mouse liver tumors induced by diethylnitrosamine (initiator alone), exhibited no Catnb mutations, while 30% of these tumors contained H-ras mutations (Aydinlik et al., 2001). Alterations of the Catnb gene and protein have also been associated with increased expression of cyclin D1 suggesting that Catnb mutation along with β-catenin protein accumulation and the resulting activation of the Wnt signaling pathway lead to an increase in cyclin D1 expression (Anna et al., 2003). Cyclin D1 protein is overexpressed in approximately 40% of human HCC and 34% of mouse hepatocellular neoplasms (Ito et al., 1998). In some cases overexpression is thought to be related to amplification of the cyclin D1 gene and overexpression of mRNA (Ito et al., 1998).
Deletion of Rb1 (loss of heterozygosity) is a frequent event in HCC and is typically accompanied by loss of expression of pRb (Zhang et al., 1994). It has been suggested that deletion of Rb1 is an early event in hepatocarcinogenesis, occurring in preneoplastic cirrhotic livers (Ashida et al., 1997). However, other studies suggest that deletion of Rb1 may be a late genetic alteration in HCC, associated with tumor progression (Zhang et al., 1994).
Epigenetic events including altered methylation also are involved in hepatocarcinogenesis. DLC-1 (frequently deleted in liver cancer), a putative tumor suppressor gene, was hypermethylated in some HCC cell lines and primary HCC of humans (Wong et al., 2003). Metallothionein (MT) is down-regulated in HCC and this may be related to hypermethylation of the MT-promoter (Cherian et al., 2003). HCC induced by treatment with DEN and other chemicals in F344 rats revealed increased expression of p53 and hypermethylation of p16 INK4A exon 1 in the later stages of carcinogenesis (Lim, 2002).
Neoplastic transformation of hepatocytes to HCC results from the accumulation of a significant number of genetic and epigenetic alterations and is accompanied by increased genetic instability. Currently, more than 20 cellular genes have been found to be either down- or up-regulated or mutated in HCC. However, studies suggest that multiple molecular mechanisms are involved in hepatocarcinogenesis and many of the specific target genes remain to be determined. Comprehensive elucidation of the specific genes and molecular pathways involved in neoplastic transformation of the liver will facilitate development of new strategies for diagnosis, prevention, and therapy.
|
Hepatoblastomas
|
|---|
Hepatoblastoma is the most common malignant hepatic neoplasm in children with an incidence of 1.5 cases per million children (Koesters and von Knebel Doeberitz, 2003). Most cases are sporadic and occur with a predominance in males, however some are associated with familial syndromes such as Beckwith-Wiedemann syndrome or familial adenomatous polyposis coli (FAP) (Ishak and Glunz, 1967; Steenman et al., 2000). Individual case reports have described this tumor in a number of different animal species including dogs, horses, alpacas and llamas, however, most animal cases have been described in mice (Neu, 1993; Shiga et al., 1997; Watt et al., 2001). In the mouse, spontaneous hepatoblastomas are rare but certain chemicals can induce a high incidence of this tumor type and, like its human counterpart, these often develop with a higher incidence in males (Turusov et al., 2002). Unlike their human equivalents, however, chemically induced mouse hepatoblastomas generally occur in aged rather than young animals. Despite this difference a number of similarities have been noted between mouse and human hepatoblastomas.
Alterations in the Wnt signaling pathway are involved in a high percentage of both mouse and human hepatoblastomas (Blaker et al., 1999; Koch et al., 1999; Anna et al., 2000; Jeng et al., 2000; Takayasu et al., 2001; Udatsu et al., 2001; Hayashi et al., 2003; Koesters and von Knebel Doeberitz, 2003). β-catenin is an essential component of the Wnt signaling pathway (Cadigan and Nusse, 1997) playing roles in intercellular adhesion, signal transduction and gene transcription (Nelson and Nusse, 2004). Mutations of the β-catenin gene in human hepatoblastomas have been reported to be as high as 89% (Jeng et al., 2000) while some chemically induced hepatoblastomas in mice reveal incidences of up to 100% (Anna et al., 2000; Takayasu et al., 2001). Both mouse and human hepatoblastomas have shown a high prevalence of deletion mutations affecting the GSK-3β binding region of the β-catenin gene (Takayasu et al., 2001; Taniguchi et al., 2002; Hayashi et al., 2003). Mutations in this region prevent degradation of the β-catenin protein allowing for enhanced signaling. Immunohistochemical studies in both mouse and human hepatoblastomas have confirmed these findings by showing a loss of β-catenin membrane staining along with increased cytoplasmic and nuclear staining (Blaker et al., 1999; Anna et al., 2000; Park et al., 2001). Studies looking at the expression of downstream targets, such as Cyclin D1, also suggest that Wnt-mediated signaling is indeed activated in both human (Kuniyasu et al., 1996; Takayasu et al., 2001) and mouse (Anna et al., 2003) hepatoblastomas. Interestingly, some of these same studies show that c-myc, another potential downstream target of the Wnt signaling pathway, is not elevated in either mouse or human hepatoblastomas. Additional support for involvement of the Wnt signaling pathway come from several human studies showing alterations in other key members of this pathway including both APC and AXIN (Oda et al., 1996; Taniguchi et al., 2002; Miao et al., 2003). Furthermore, people with the familial syndrome FAP (which carry a germline mutation of APC) are known to have up to a thousand times greater risk for development of hepatoblastomas as compared to the general population (Kingston et al., 1982; Koesters and von Knebel Doeberitz, 2003).
Beyond the Wnt signaling pathway few molecular analyses on mouse hepatoblastomas have been performed. A couple of mouse studies report that ras mutations are uncommon as are alterations in p53 (Devereux et al., 1994; Hayashi et al., 2003). Similarly, most studies on human hepatoblastomas have shown a lack of p53 involvement (Chen et al., 1995) although only a few studies, involving a small number of cases, have looked at RAS mutations in human hepatoblastomas. One study found a single K-RAS mutation in codon 12 from 1 human hepatoblastoma (Stork et al., 1991) and another found no mutations in 2 cases that were examined (Tada et al., 1990).
TGF- is a potent stimulator of cell proliferation in the liver and its overexpression is thought to be important in hepatocarcinogenesis. In the mouse, TGF- expression was shown to be elevated in chemically induced hepatoblastomas and the levels were even higher than those found in hepatocellular carcinomas (Sakairi et al., 2001). Similar findings have been described in human hepatoblastomas where TGF- expression was shown to be inversely correlated with the level of cell proliferation and positively correlated with the degree of differentiation (Kiss et al., 1998). An additional growth factor frequently implicated in human hepatoblastomas is IGF II. Up-regulation of IGF II has been described in a high percentage of human hepatoblastomas (Li et al., 1995; Hartmann et al., 2000) and although the exact mechanism for this alteration is not entirely certain it appears that loss of imprinting and/or promoter demethylation are at least partly involved (Eriksson et al., 2001; Zatkova et al., 2004). Other studies have shown that the level of IGF II expression in these tumors is inversely correlated with the degree of tumor differentiation (Akmal et al., 1995). Histologically, chemically-induced mouse hepatoblastomas frequently appear similar to the less differentiated human hepatoblastoma subtypes (embryonal or small cell) (Turusov et al., 1973; Diwan et al., 1995), however, to our knowledge, IGF II’s involvement in chemically induced mouse hepatoblastomas has not been thoroughly explored. Interestingly, activation of the IGF II receptor has been shown to result in redistribution of β-catenin from the cell membrane to the nucleus and cause intracellular sequestration and degradation of E-cadherin (Morali et al., 2001). Other studies have shown a decrease in E-cadherin membrane expression in both mouse (Anna et al., 2003) and human hepatoblastomas (von Schweinitz et al., 1996).
A few studies have looked at the role of growth factor receptors in hepatoblastomas including c-MET (hepatocyte growth factor receptor), which was reported as being overexpressed in human hepatoblastomas (von Schweinitz et al., 2002), and epidermal growth factor receptor (EGF-R), which was reported as showing reduced expression in some chemically induced mouse hepatoblastomas (Anna et al., 2003). Interestingly, both EGF-R (Hoschuetzky et al., 1994; Takahashi et al., 1997) and c-MET (Danilkovitch-Miagkova et al., 2001; Nelson and Nusse, 2004) are also involved in regulation of β-catenin.
Although a number of different chromosomal alterations have been described in human hepatoblastomas these are not as common as those found in hepatocellular carcinomas (Buendia, 2002). In addition, it appears as though the presence of β-catenin mutations in either of these tumor types is associated with chromosomal stability (Buendia, 2002). Cell cycle inhibitors have been studied to a limited extent in human but not mouse hepatoblastomas. p16 was shown to be down-regulated due to hypermethylation (Shim et al., 2003) and p27 exhibited reduced expression in undifferentiated hepatoblastomas (Brotto and Finegold, 2002).
|
Conclusions
|
|---|
Mouse liver carcinogenesis is a complex process which involves growth factors, oncogenes, tumor suppressor genes, cell cycle genes and other mechanisms such as receptor based signal transduction pathways (Figure 1). In addition, factors such as altered methylation and chromosomal alterations may contribute to liver cancer. As more information is obtained on the multiple factors which contribute to the progression of liver cancer in mice and humans, it will provide opportunities for successful intervention and treatment strategies.
|
References
|
|---|
- Akmal, SN, Yun, K, MacLay, J, Higami, Y, & Ikeda, T. (1995). Insulin-like growth factor 2 and insulin-like growth factor binding protein 2 expression in hepatoblastoma. Hum Pathol, 26(8), 846-51[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Anna, CH, Iida, M, Sills, RC, & Devereux, TR. (2003). Expression of potential β-catenin targets, cyclin D1, c-Jun, c-Myc, E-cadherin, and EGFR in chemically induced hepatocellular neoplasms from B6C3F1 mice. Toxicol Appl Pharmacol, 190(2), 135-45[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Anna, CH, Sills, RC, Foley, JF, Stockton, PS, Ton, TV, & Devereux, TR. (2000). β-catenin mutations and protein accumulation in all hepatoblastomas examined from B6C3F1 mice treated with anthraquinone or oxazepam. Cancer Res, 60(11), 2864-8[Abstract/Free Full Text]
- Ashida, K, Kishimoto, Y, Nakamoto, K, Wada, K, Shiota, G, Hirooka, Y, Kamisaki, Y, Itoh, T, & Kawasaki, H. (1997). Loss of heterozygosity of the retinoblastoma gene in liver cirrhosis accompanying hepatocellular carcinoma. J Cancer Res Clin Oncol, 123(9), 489-95[Web of Science][Medline]
[Order article via Infotrieve]
- Aydinlik, H, Nguyen, TD, Moennikes, O, Buchmann, A, & Schwarz, M. (2001). Selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of β-catenin-mutated mouse liver tumors. Oncogene, 20 (53), 7812-6[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Blaker, H, Hofmann, WJ, Rieker, RJ, Penzel, R, Graf, M, & Otto, HF. (1999). β-catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma. Genes Chromosomes Cancer, 25(4), 399-402[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Brotto, M, & Finegold, MJ. (2002). Distinct patterns of p27/KIP 1 gene expression in hepatoblastoma and prognostic implications with correlation before and after chemotherapy. Hum Pathol, 33(2), 198-205[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Buendia, MA. (2002). Genetic alterations in hepatoblastoma and hepatocellular carcinoma: common and distinctive aspects. Med Pediatr Oncol, 39(5), 530-5[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Cadigan, KM, & Nusse, R. (1997). Wnt signaling: a common theme in animal development. Genes Dev, 11(24), 3286-305[Free Full Text]
- Chen, TC, Hsieh, LL, & Kuo, TT. (1995). Absence of p53 gene mutation and infrequent overexpression of p53 protein in hepatoblastoma. J Pathol, 176(3), 243-7[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Cherian, MG, Jayasurya, A, & Bay, BH. (2003). Metallothioneins in human tumors and potential roles in carcinogenesis. Mutat Res, 533(1–2), 201-9[Medline]
[Order article via Infotrieve]
- Coleman, WB. (2003). Mechanisms of human hepatocarcinogenesis. Curr Mol Med, 3(6), 573-88[CrossRef]
- Danilkovitch-Miagkova, A, Miagkov, A, Skeel, A, Nakaigawa, N, Zbar, B, & Leonard, EJ. (2001). Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the β-catenin pathway. Mol Cell Biol, 21 (17), 5857-68[Abstract/Free Full Text]
- Devereux, TR, Anna, CH, Foley, JF, White, CM, Sills, RC, & Barrett, JC. (1999). Mutation of beta-catenin is an early event in chemically induced mouse hepatocellular carcinogenesis. Oncogene, 18(33), 4726-33[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Devereux, TR, Foley, JF, Maronpot, RR, Kari, F, & Anderson, MW. (1993). Ras proto-oncogene activation in liver and lung tumors from B6C3F1 mice exposed chronically to methylene chloride. Carcinogenesis, 14 (5), 795-801[Abstract/Free Full Text]
- Devereux, TR, White, CM, Sills, RC, Bucher, JR, Maronpot, RR, & Anderson, MW. (1994). Low frequency of H-ras mutations in hepatocellular adenomas and carcinomas and in hepatoblastomas from B6C3F1 mice exposed to oxazepam in the diet. Carcinogenesis, 15(5), 1083-7[Abstract/Free Full Text]
- Diwan, BA, Henneman, JR, & Rice, JM. (1995). Further evidence for promoter-dependent development of hepatoblastoma in the mouse. Cancer Lett, 89(1), 29-35[Web of Science][Medline]
[Order article via Infotrieve]
- Eriksson, T, Frisk, T, Gray, SG, von Schweinitz, D, Pietsch, T, Larsson, C, Sandstedt, B, & Ekstrom, TJ. (2001). Methylation changes in the human IGF2 p3 promoter parallel IGF2 expression in the primary tumor, established cell line, and xenograft of a human hepatoblastoma. Exp Cell Res, 270(1), 88-95[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Fausto, N. (1999). Mouse liver tumorigenesis: models, mechanisms, and relevance to human disease. Semin Liver Dis, 19(3), 243-52[Web of Science][Medline]
[Order article via Infotrieve]
- Hainaut, P, Hernandez, T, Robinson, A, Rodriguez-Tome, P, Flores, T, Hollstein, M, Harris, CC, & Montesano, R. (1998). IARC Database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualisation tools. Nucleic Acids Res, 26(1), 205-13[Abstract/Free Full Text]
- Harada, T, Enomoto, A, Boorman, GA, & Maronpot, RR. In Maronpot, RR (Ed.). (1999). Liver and Gallbladder. Pathology of the Mouse (pp.119-83). Illinois: Cache River Press
- Hartmann, W, Waha, A, Koch, A, Goodyer, CG, Albrecht, S, von Schweinitz, D, & Pietsch, T. (2000). p57(KIP2) is not mutated in hepatoblastoma but shows increased transcriptional activity in a comparative analysis of the three imprinted genes p57(KIP2), IGF2, and H19. Am J Pathol, 157(4), 1393-403[Abstract/Free Full Text]
- Hayashi, SM, Ton, TV, Hong, HH, Irwin, RD, Haseman, JK, Devereux, TR, & Sills, RC. (2003). Genetic alterations in the Catnb gene but not the H-ras gene in hepatocellular neoplasms and hepatoblastomas of B6C3F(1) mice following exposure to diethanolamine for 2 years. Chem Biol Interact, 146(3), 251-61[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hoschuetzky, H, Aberle, H, & Kemler, R. (1994). β-catenin mediates the interaction of the cadherin-catenin complex with epidermal growth factor receptor. J Cell Biol, 127(5), 1375-80[Abstract/Free Full Text]
- Hsu, HC, Tseng, HJ, Lai, PL, Lee, PH, & Peng, SY. (1993). Expression of p53 gene in 184 unifocal hepatocellular carcinomas: association with tumor growth and invasiveness. Cancer Res, 53(19), 4691-4[Abstract/Free Full Text]
- Huynh, H. (2004). Overexpression of tumour suppressor retinoblastoma 2 protein (pRb2/p130) in hepatocellular carcinoma. Carcinogenesis. in press. in press. in press.
- Ishak, KG, & Glunz, PR. (1967). Hepatoblastoma and hepatocarcinoma in infancy and childhood. Report of 47 cases. Cancer, 20(3), 396-422[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ito, Y, Sasaki, Y, Horimoto, M, Wada, S, Tanaka, Y, Kasahara, A, Ueki, T, Hirano, T, Yamamoto, H, Fujimoto, J, Okamoto, E, Hayashi, N, & Hori, M. (1998). Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology, 27(4), 951-8[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Jeng, YM, Wu, MZ, Mao, TL, Chang, MH, & Hsu, HC. (2000). Somatic mutations of β-catenin play a crucial role in the tumorigenesis of sporadic hepatoblastoma. Cancer Lett, 152(1), 45-51[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Kingston, JE, Draper, GJ, & Mann, JR. (1982). Hepatoblastoma and polyposis coli. Lancet, 1(8269), 457[Web of Science][Medline]
[Order article via Infotrieve]
- Kiss, A, Szepesi, A, Lotz, G, Nagy, P, & Schaff, Z. (1998). Expression of transforming growth factor-alpha in hepatoblastoma. Cancer, 83(4), 690-7[Medline]
[Order article via Infotrieve]
- Koch, A, Denkhaus, D, Albrecht, S, Leuschner, I, von Schweinitz, D, & Pietsch, T. (1999). Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the β-catenin gene. Cancer Res, 59(2), 269-73[Abstract/Free Full Text]
- Koesters, R, & von Knebel Doeberitz, M. (2003). The Wnt signaling pathway in solid childhood tumors. Cancer Lett, 198(2), 123-38[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Kuniyasu, H, Yasui, W, Shimamoto, F, Fujii, K, Nakahara, M, Asahara, T, Dohi, K, & Tahara, E. (1996). Hepatoblastoma in an adult associated with c-met proto-oncogene imbalance. Pathol Int, 46(12), 1005-10[Web of Science][Medline]
[Order article via Infotrieve]
- Lahm, H, Gittner, K, Krebs, O, Sprague, L, Deml, E, Oesterle, D, Hoeflich, A, Wanke, R, & Wolf, E. (2002). Diethylnitrosamine induces long-lasting re-expression of insulin-like growth factor II during early stages of liver carcinogenesis in mice. Growth Horm IGF Res, 12(1), 69-79[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Li, X, Adam, G, Cui, H, Sandstedt, B, Ohlsson, R, & Ekstrom, TJ. (1995). Expression, promoter usage and parental imprinting status of insulin-like growth factor II (IGF2) in human hepatoblastoma: uncoupling of IGF2 and H19 imprinting. Oncogene, 11(2), 221-9[Web of Science][Medline]
[Order article via Infotrieve]
- Lim, IK. (2002). Spectrum of molecular changes during hepatocarcinogenesis induced by DEN and other chemicals in Fischer 344 male rats. Mech Ageing Dev, 123(12), 1665-80[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Liu, YP, Lin, Y, & Ng, ML. (1996). Immunochemical and genetic analysis of the p53 gene in liver preneoplastic nodules from aflatoxin-induced rats in one year. Ann Acad Med Singapore, 25(1), 31-6[Medline]
[Order article via Infotrieve]
- Macdonald, GA, Greenson, JK, Saito, K, Cherian, SP, Appelman, HD, & Boland, CR. (1998). Microsatellite instability and loss of heterozy-gosity at DNA mismatch repair gene loci occurs during hepatic carcinogenesis. Hepatology, 28(1), 90-7[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Mathers, CD, Shibuya, K, Boschi-Pinto, C, Lopez, AD, & Murray, CJ. (2002). Global and regional estimates of cancer mortality and incidence by site: I. Application of regional cancer survival model to estimate cancer mortality distribution by site. BMC Cancer, 2(1), 36[CrossRef][Medline]
[Order article via Infotrieve]
- Miao, J, Kusafuka, T, Udatsu, Y, & Okada, A. (2003). Sequence variants of the Axin gene in hepatoblastoma. Hepatol Res, 25(2), 174-9[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Mise, K, Tashiro, S, Yogita, S, Wada, D, Harada, M, Fukuda, Y, Miyake, H, Isikawa, M, Izumi, K, & Sano, N. (1998). Assessment of the biological malignancy of hepatocellular carcinoma: relationship to clinicopathological factors and prognosis. Clin Cancer Res, 4(6), 1475-82[Abstract]
- Morali, OG, Delmas, V, Moore, R, Jeanney, C, Thiery, JP, & Larue, L. (2001). IGF-II induces rapid β-catenin relocation to the nucleus during epithelium to mesenchyme transition. Oncogene, 20(36), 4942-50[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Nelson, WJ, & Nusse, R. (2004). Convergence of Wnt, β-catenin, and cadherin pathways. Science, 303(5663), 1483-7[Abstract/Free Full Text]
- Neu, SM. (1993). Hepatoblastoma in an equine fetus. J Vet Diagn Invest, 5(4), 634-7[Free Full Text]
- Nhieu, JT, Renard, CA, Wei, Y, Cherqui, D, Zafrani, ES, & Buendia, MA. (1999). Nuclear accumulation of mutated β-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol, 155(3), 703-10[Abstract/Free Full Text]
- Oda, H, Imai, Y, Nakatsuru, Y, Hata, J, & Ishikawa, T. (1996). Somatic mutations of the APC gene in sporadic hepatoblastomas. Cancer Res, 56(14), 3320-3[Abstract/Free Full Text]
- Parada, LA, Hallen, M, Tranberg, KG, Hagerstrand, I, Bondeson, L, Mitelman, F, & Johansson, B. (1998). Frequent rearrangements of chromosomes 1, 7, and 8 in primary liver cancer. Genes Chromosomes Cancer, 23 (1), 26-35[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Park, WS, Oh, RR, Park, JY, Kim, PJ, Shin, MS, Lee, JH, Kim, HS, Lee, SH, Kim, SY, Park, YG, An, WG, Jang, JJ, Yoo, NJ, & Lee, JY. (2001). Nuclear localization of β-catenin is an important prognostic factor in hepatoblastoma. J Pathol, 193(4), 483-90[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Parkin, DM, Pisani, P, & Ferlay, J. (1999). Global cancer statistics. CA Cancer J Clin, 49(1), 33-64. 1. 1. 1.[Abstract/Free Full Text]
- Puisieux, A, Lim, S, Groopman, J, & Ozturk, M. (1991). Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens. Cancer Res, 51(22), 6185-9[Abstract/Free Full Text]
- Saito, Y, Kanai, Y, Sakamoto, M, Saito, H, Ishii, H, & Hirohashi, S. (2002). Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis. Proc Natl Acad Sci USA, 99(15), 10060-5[Abstract/Free Full Text]
- Sakairi, T, Kobayashi, K, Goto, K, Okada, M, Kusakabe, M, Tsuchiya, T, Sugimoto, J, Sano, F, & Mutai, M. (2001). Greater expression of transforming growth factor alpha and proliferating cell nuclear antigen staining in mouse hepatoblastomas than hepatocellular carcinomas induced by a diethylnitrosamine-sodium phenobarbital regimen. Toxicol Pathol, 29(4), 479-82[Abstract/Free Full Text]
- Shiga, A, Shirota, K, Shida, T, Yamada, T, & Nomura, Y. (1997). Hepatoblastoma in a dog. J Vet Med Sci, 59(12), 1167-70[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Shim, YH, Park, HJ, Choi, MS, Kim, JS, Kim, H, Kim, JJ, Jang, JJ, & Yu, E. (2003). Hypermethylation of the p16 gene and lack of p16 expression in hepatoblastoma. Mod Pathol, 16(5), 430-6[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Steenman, M, Westerveld, A, & Mannens, M. (2000). Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways. Genes Chromosomes Cancer, 28(1), 1-13[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Stork, P, Loda, M, Bosari, S, Wiley, B, Poppenhusen, K, & Wolfe, H. (1991). Detection of K-ras mutations in pancreatic and hepatic neoplasms by non-isotopic mismatched polymerase chain reaction. Oncogene, 6(5), 857-62[Web of Science][Medline]
[Order article via Infotrieve]
- Tada, M, Omata, M, & Ohto, M. (1990). Analysis of ras gene mutations in human hepatic malignant tumors by polymerase chain reaction and direct sequencing. Cancer Res, 50(4), 1121-4[Abstract/Free Full Text]
- Takahashi, K, Suzuki, K, & Tsukatani, Y. (1997). Induction of tyrosine phos-phorylation and association of beta-catenin with EGF receptor upon tryptic digestion of quiescent cells at confluence. Oncogene, 15(1), 71-8[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Takayasu, H, Horie, H, Hiyama, E, Matsunaga, T, Hayashi, Y, Watanabe, Y, Suita, S, Kaneko, M, Sasaki, F, Hashizume, K, Ozaki, T, Furuuchi, K, Tada, M, Ohnuma, N, & Nakagawara, A. (2001). Frequent deletions and mutations of the β-catenin gene are associated with overexpression of cyclin D1 and fibronectin and poorly differentiated histology in childhood hepatoblastoma. Clin Cancer Res, 7(4), 901-8[Abstract/Free Full Text]
- Taniguchi, K, Roberts, LR, Aderca, IN, Dong, X, Qian, C, Murphy, LM, Nagorney, DM, Burgart, LJ, Roche, PC, Smith, DI, Ross, JA, & Liu, W. (2002). Mutational spectrum of β-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene, 21(31), 4863-71[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Turusov, VS, Deringer, MK, Dunn, TB, & Stewart, HL. (1973). Malignant mouse-liver tumors resembling human hepatoblastomas. J Natl Cancer Inst, 51(5), 1689-95[Web of Science][Medline]
[Order article via Infotrieve]
- Turusov, VS, Torii, M, Sills, RC, Willson, GA, Herbert, RA, Hailey, JR, Haseman, JK, & Boorman, GA. (2002). Hepatoblastomas in mice in the US National Toxicology Program (NTP) studies. Toxicol Pathol, 30(5), 580-91[Abstract/Free Full Text]
- Udatsu, Y, Kusafuka, T, Kuroda, S, Miao, J, & Okada, A. (2001). High frequency of β-catenin mutations in hepatoblastoma. Pediatr Surg Int, 17(7), 508-12[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- von Schweinitz, D, Kraus, JA, Albrecht, S, Koch, A, Fuchs, J, & Pietsch, T. (2002). Prognostic impact of molecular genetic alterations in hepatoblastoma. Med Pediatr Oncol, 38(2), 104-8[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- von Schweinitz, D, Leuschner, I, Gluer, S, & Pietsch, T. (1996). Expression of cell adhesion molecules and common acute lymphoblastic leukaemia antigen in hepatoblastoma. Virchows Arch, 429(4–5), 235-41[Web of Science][Medline]
[Order article via Infotrieve]
- Watt, BC, Cooley, AJ, & Darien, BJ. (2001). Congenital hepatoblastoma in a neonatal alpaca cria. Can Vet J, 42(11), 872-4[Web of Science][Medline]
[Order article via Infotrieve]
- Weihrauch, M, Benick, M, Lehner, G, Wittekind, M, Bader, M, Wrbitzk, R, & Tannapfel, A. (2001). High prevalence of K-ras-2 mutations in hepatocellular carcinomas in workers exposed to vinyl chloride. Int Arch Occup Environ Health, 74(6), 405-10[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Wong, CM, Lee, JM, Ching, YP, Jin, DY, & Ng, IO. (2003). Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. Cancer Res, 63(22), 7646-51[Abstract/Free Full Text]
- Yamamoto, Y, Sakamoto, M, Fujii, G, Tsuiji, H, Kenetaka, K, Asaka, M, & Hirohashi, S. (2003). Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with β-catenin mutations. Hepatology, 37(3), 528-33[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Zatkova, A, Rouillard, JM, Hartmann, W, Lamb, BJ, Kuick, R, Eckart, M, von Schweinitz, D, Koch, A, Fonatsch, C, Pietsch, T, Hanash, SM, & Wimmer, K. (2004). Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma. Genes Chromosomes Cancer, 39(2), 126-37[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Zhang, X, Xu, HJ, Murakami, Y, Sachse, R, Yashima, K, Hirohashi, S, Hu, SX, Benedict, WF, & Sekiya, T. (1994). Deletions of chromosome 13q, mutations in Retinoblastoma 1, and retinoblastoma protein state in human hepatocellular carcinoma. Cancer Res, 54(15), 4177-82[Abstract/Free Full Text]
- Zhu, H, Wang, Y, Chen, J, Cheng, G, & Xue, J. (2004). Transgenic mice expressing hepatitis B virus X protein are more susceptible to carcinogen induced hepatocarcinogenesis. Exp Mol Pathol, 76(1), 44-50[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
Toxicologic Pathology, Vol. 33, No. 1,
175-180 (2005)
DOI: 10.1080/01926230590522130
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
B.-R. Wei, J. B. Edwards, S. B. Hoover, H. S. Tillman, L. T. Reed, R. C. Sills, and R. M. Simpson
Altered {beta}-Catenin Accumulation in Hepatocellular Carcinomas of Diethylnitrosamine-Exposed Rhesus Macaques
Toxicol Pathol,
December 1, 2008;
36(7):
972 - 980.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. A. Schmidt, C. S. Chiariello, E. Capilla, F. Miller, and W. F. Bahou
Development of Hepatocellular Carcinoma in Iqgap2-Deficient Mice Is IQGAP1 Dependent
Mol. Cell. Biol.,
March 1, 2008;
28(5):
1489 - 1502.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kushida, S. Aiso, K. Morimura, M. Wei, H. Wanibuchi, K. Nagano, and S. Fukushima
Absence of {beta}-Catenin Alteration in Hepatic Tumors Induced by p-Nitroanisole in Crj:BDF1 Mice
Toxicol Pathol,
April 1, 2006;
34(3):
237 - 242.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
TOP
Abstract
Hepatocellular Neoplasms