Hepatocyte death in hepatocarcinogenesis

Pitot, Henry C.

doi:10.1002/hep.510280101

Cited by 42 publications

(26 citation statements)

References 71 publications

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“…However, our study demonstrated that apoptotic cells increased with time. These findings suggest that different apoptosis signaling pathways other than TGF-signaling pathway, such as Fas/ Fas ligand pathway, might have significant roles in chemical hepatocarcinogenesis of rat, especially late times of promotion stage (34). Also, our study showed that apoptotic cells are more numerous in adjacent liver parenchyme than in preneoplastic lesions.…”

Section: Discussionsupporting

confidence: 54%

Expression and Localization of the Transforming Growth Factor-beta Type I receptor and Smads in Preneoplastic Lesions during Chemical Hepatocarcinogenesis in Rats

et al. 2003

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Little is known about the involvement of Smad-related molecules in the regulation of the Transforming Growth Factor (TGF)-signaling pathway during hepatocarcinogenesis, particularly with respect to preneoplastic lesions of a rat liver. The aims of this study were to investigate the localizations and temporal expressions of TGF-Receptor Type 1 (TGR1) and Smads during the promotion stage of chemical hepatocarcinogenesis in rats. We investigated expressions and localizations of TGR1, Smad2, Smad4, and Smad7 by using semi-quantitative RT-PCR and immunohistochemistry in preneoplastic lesions during rat chemical hepatocarcinogenesis induced by Solt and Farber's method. The down-regulation of TGR1, Smad2, and Smad4 was evident during the later steps of the promotion stage of chemical hepatocarcinogenesis. In contrast with other Smads, increased Smad7 expression was evident during the later steps of the promotion stage. Also immunohistochemistry revealed that the main site of TGR1, Smad2, Smad4, and Smad7 expression was mainly in hepatocytes of the preneoplastic lesions of a rat liver. Dysregulation of the downstream effectors of TGF-such as TGR1, Smad2, Smad4 and, Smad7 might contribute to the progression of preneoplastic lesions during chemical hepatocarcinogenesis in a rat.

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Section: Discussionsupporting

confidence: 54%

Expression and Localization of the Transforming Growth Factor-beta Type I receptor and Smads in Preneoplastic Lesions during Chemical Hepatocarcinogenesis in Rats

et al. 2003

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“…Rat GST-P, which belongs to class pi in the species-independent classification of GST, has been shown to be a marker enzyme for rat preneoplastic lesions (48). Rat chemical hepatocarcinogenesis comprises 3 stages; initiation, promotion and progression (49), and GST-P is strongly expressed in rat preneoplastic lesions such as enzyme-altered foci, which emerge in the promotion stage. Preneoplastic enzyme-altered foci have been proposed to play a key role in the process of hepatocarcinogenesis (48).…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor effects of cimetidine on hepatocellular carcinomas in diethylnitrosamine-treated rats

Furuta

Sato²,

Miyake³

et al. 2008

Oncol Rep

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Abstract. Cimetidine is known to have an anti-tumor effect on certain types of malignancies, though on hepatocellular carcinomas (HCCs), its effect remains unclear. We studied the anti-tumor effects of cimetidine on chemically-induced HCCs in rats. Four-week-old male Wistar rats (n=105) were divided into 4 groups. Those in groups A and B were administered diethylnitrosamine (DEN) intraperitoneally at 100 mg/kg body weight every week for 6 weeks, during which rats in group A were given tap water and those in group B received cimetidine (100 mg/kg/day) in their drinking water. Rats in groups C and D were administered saline instead of DEN and given tap water with 100 mg/kg/day of cimetidine, respectively. The animals were sacrificed at 7, 12, 22 and 32 weeks after the first administration of drugs and examined. Liver nodules were observed only in groups A and B, with the number of nodules, maximum diameter of the largest nodule, and liver weight significantly lower in group B. Immunohistochemistry findings showed that glutathione S-transferase placental-positive preneoplastic foci were significantly decreased in group B. Cimetidine treatment decreased the number of proliferating cell nuclear antigen-positive hepatocytes and tended to enhance natural killer (NK) cell activity in splenic lymphocytes. In addition, flow cytometry revealed that the proportion of NK cells among total splenic lympocytes was not affected by cimetidine treatment. Our results showed that cimetidine has an inhibiting effect on hepatocarcinogenesis.

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“…These characteristics handicap in vivo studies. 12,13 Regulation of apoptosis has been studied in hepatoma but there are few studies of spontaneous apoptosis in primary cultures of hepatocytes which are known to die spontaneously, at least in part, by apoptosis with increasing time in culture. 14 ± 16 Although glucocorticoids induce rapid apoptosis in susceptible thymocyte and lymphocyte populations, several studies have demonstrated the inhibitory effects of glucocorticoids against apoptosis in various models: (i) DEX inhibits spontaneous as well as TNF-a-induced human neutrophil apoptosis, 17 ± 19 (ii) DEX and hydrocortisone abolish tumour necrosis factor a (TNFa)-induced cytoxicity of several tumour cell lines via inhibition of phospholipase A 2 activity, 20,21 and (iii) DEX inhibits spontaneous apoptosis and transforming growth factor b 1 -induced apoptosis in rat hepatoma cells via Bcl-xL induction.…”

Section: Apoptosismentioning

confidence: 99%

Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction

Bailly-Maître¹,

Sousa²,

Boulukos³

et al. 2001

Cell Death Differ

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We examined the effects of dexamethasone (DEX) on the apoptotic process in primary cultures of human and rat hepatocytes. DEX prolonged cell viability, inhibited the development of an apoptotic morphology, and stabilised the expression of procaspase-3 in both human and rat hepatocytes. In addition, the inhibition of apoptosis by DEX was strongly correlated with a decrease of caspase-3-like protease activity. Moreover, DEX treatment increased the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins in human and rat hepatocytes, respectively, whereas the expression of pro-apoptotic proteins Bcl-xS or Bad was not detected or remained unchanged. The bcl-xL transcript is regulated at the transcriptional level and its expression paralleled that of Bcl-xL protein in DEX-treated rat hepatocytes. Taken together, these results indicate that this glucocorticoid exerts a protective role on cell survival and it delays apoptosis of human and rat hepatocytes by modulating caspase-3-like protease activity and bcl-2 and bcl-x gene expression. Cell Death and Differentiation (2001) 8, 279 ± 288.

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Hepatocyte death in hepatocarcinogenesis

Cited by 42 publications

References 71 publications

Expression and Localization of the Transforming Growth Factor-beta Type I receptor and Smads in Preneoplastic Lesions during Chemical Hepatocarcinogenesis in Rats

Expression and Localization of the Transforming Growth Factor-beta Type I receptor and Smads in Preneoplastic Lesions during Chemical Hepatocarcinogenesis in Rats

Anti-tumor effects of cimetidine on hepatocellular carcinomas in diethylnitrosamine-treated rats

Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction

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