Alterations of the Transforming Growth Factor‐(β Signaling Pathway in Hepatocellular Carcinomas Induced Endogenously and Exogenously in Rats

Sasaki, Yasutaka; Tsujiuchi, Toshifumi; Murata, Nao; Tsutsumi, Masahiro; Konishi, Yoichi

doi:10.1111/j.1349-7006.2001.tb01042.x

Cited by 12 publications

(11 citation statements)

References 40 publications

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“…Moreover, we have recently found that there are differences between exogenous and endogenous mechanisms underlying rat hepatocarcinogenesis. 30,31) However, the present results showed that the decreased Bcl-x expression was observed in the experimental models with both DEN and CDAA diet, which have been widely used in studies on hepatocarcinogenesis, suggesting that, similar to the increase in GST-P protein, the decrease in Bcl-x protein may be a common event for at least rat preneoplastic lesions induced exogenously and endogenously. The appearance of preneoplastic cells with decreased Bcl-x expression also seems to be more delayed than that of the increased GST-P expression.…”

Section: Discussionmentioning

confidence: 50%

Decreased Expression of Bcl‐x Protein during Hepatocarcinogenesis Induced Exogenously and Endogenously in Rats

Hatanaka¹,

Nakae²,

Mutai³

et al. 2001

Japanese Journal of Cancer Research

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Dysregulations of apoptosis have been widely recognized as important events in multi-stage carcinogenesis. Bcl-x, a member of the Bcl-2 family, is known to act as a regulator of apoptosis. The present study was conducted to assess the role of altered Bcl-x protein expression in exogenous and endogenous hepatocarcinogenesis in rats. In the short-term exogenous models, male Fischer 344 rats, 6 weeks old, were given a single intraperitoneal injection of diethylnitrosamine (DEN) at a dose of 200 mg/kg body weight, partially hepatectomized at the end of week 3, administered phenobarbital at a concentration of 0.05% from the end of week 2 for 6 weeks, and sacrificed. In the livers, glutathione S-transferase (GST-P)-positive, putative preneoplastic lesions were induced, and Bcl-x protein expression was decreased in 24.7% of such lesions. The incidence of GST-P-positive lesions with decreased Bcl-x increased depending on the size of the lesions; 18.9%, 32.4% and 86.5% in the lesions smaller than 0.03, between 0.03 and 0.3, and larger than 0.3 mm 2 , respectively. In GST-P-positive lesions larger than 0.3 mm 2 , both apoptosis induction and cell proliferation activity were enhanced when Bcl-x protein expression was decreased. In the long-term exogenous models, rats were given 10 mg/kg of DEN, partially hepatectomized 4 h after treatment, administered 0.5 mg/kg of colchicine at the end of days 1 and 3, subjected to a selection procedure, and sacrificed at the end of week 45. Hepatocellular carcinomas were induced with the decreased Bcl-x protein expression. In the endogenous model, rats were fed a choline-deficient, L-amino aciddefined diet for 16 or 80 weeks and sacrificed. Bcl-x protein expression was decreased both in GST-P-positive lesions and hepatocellular carcinoma. These results suggest that this decrease of Bcl-x protein might serve as an indicator of the advanced form of preneoplastic lesions, and that this decrease could also be associated with a potential to progress into carcinoma in both exogenous and endogenous hepatocarcinogenesis of rats.

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Section: Discussionmentioning

confidence: 50%

Decreased Expression of Bcl‐x Protein during Hepatocarcinogenesis Induced Exogenously and Endogenously in Rats

Hatanaka¹,

Nakae²,

Mutai³

et al. 2001

Japanese Journal of Cancer Research

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“…This indicates the possibility that the TGF-␤1 signaling pathway is disturbed in preneoplastic nodules induced by a CDAA diet [37,38]. TGF-␤1 is produced as a small, biologically inactive, latent complex, which consists of mature TGF-␤1 and latency-associated peptide (LAP).…”

Section: Discussionmentioning

confidence: 99%

Enhanced expression of growth factors and imbalance between hepatocyte proliferation and apoptosis in the livers of rats fed a choline-deficient, ?-amino acid-defined diet

Onaga

Ido

Hasuike

et al. 2004

Hepatology Research

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“…Thus, it has been suggested that inactivation of the Smad4 gene might play a role in pancreatic cancer and possibly other human cancers. In the case of rodents, we previously reported a low frequency of Smad4 mutations in rat lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine (8.3%) (22) and no mutations in rat hepatocellular carcinomas induced by Nnitrosodiethylamine (29). The present study showed only one mutation in 12 hamster PDAs and three established cell lines.…”

Section: Discussionmentioning

confidence: 59%

Alterations in the Smad4 gene in hamster pancreatic duct adenocarcinomas and established cell lines

Shimizu

Kitahashi²,

Fujii³

et al. 2006

Oncol Rep

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Abstract. Alterations of the Smad4 gene, identified as a mediator of the transforming growth factor-ß pathway, were investigated in hamster pancreatic duct adenocarcinomas (PDAs) and established cell lines. Female Syrian golden hamsters received 70 mg/kg of N-nitrosobis(2-oxopropyl)amine (BOP) followed by repeated exposure to an augmentation pressure regimen consisting of a choline-deficient diet combined with DL-ethionine then L-methionine and a further administration of 20 mg/kg BOP. A total of 12 PDAs obtained 10 weeks after beginning the experiment and three cell lines established from subcutaneously transplantable PDAs in syngeneic hamsters were examined for mutations using reverse transcription-polymerase chain reaction-single strand conformation polymorphism (RT-PCR-SSCP) analysis. A mutation was detected in only one PDA (1/12, 8.3%) in the form of an ACC to ATC (Thr to IIe) transition at codon 73; none were detected in the three cell lines. No reduced or increased expression of the Smad4 gene was detected in any case using real-time quantitative RT-PCR. These results suggest that the Smad4 gene might play a role in limited fraction of BOP-induced pancreatic duct carcinogenesis in hamsters.

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Alterations of the Transforming Growth Factor‐(β Signaling Pathway in Hepatocellular Carcinomas Induced Endogenously and Exogenously in Rats

Cited by 12 publications

References 40 publications

Decreased Expression of Bcl‐x Protein during Hepatocarcinogenesis Induced Exogenously and Endogenously in Rats

Decreased Expression of Bcl‐x Protein during Hepatocarcinogenesis Induced Exogenously and Endogenously in Rats

Enhanced expression of growth factors and imbalance between hepatocyte proliferation and apoptosis in the livers of rats fed a choline-deficient, ?-amino acid-defined diet

Alterations in the Smad4 gene in hamster pancreatic duct adenocarcinomas and established cell lines

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