Gene Activation and Deactivation during Multistage Hepatocarcinogenesis in the Rat

Pitot, Henry C.; Neveu, Mark J.; Hully, James R.; Sargent, Linda M.; Paul, David L.; Nicholson, Bruce J.

doi:10.1007/978-1-4615-3694-9_6

Cited by 3 publications

(2 citation statements)

References 59 publications

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“…According to a genetic model of hepatocarcinogenesis [1,2], the initiation stage is characterized by point mutations in oncogenes or tumor suppressor genes. Some reversible changes such as increase in DNA synthesis, overexpression of growth-related genes, and infrequent cell loss by apoptosis occur during the clonal expansion of initiated cells (promotion).…”

Section: Introductionmentioning

confidence: 99%

Correlation of c-myc overexpression and amplification with progression of preneoplastic liver lesions to malignancy in the poorly susceptible wistar rat strain

et al. 1999

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Persistent liver nodules (PNs) and hepatocellular carcinomas (HCCs) induced in F344 rats by the resistant hepatocyte (RH) model exhibit c-myc overexpression and amplification. The role of these changes in progression of PN was investigated in nodules with different propensities to evolve to HCC in resistant Wistar rats and, for comparison, in susceptible F344 rats. Initiation of rats with diethylnitrosamine was followed by selection with 2-acetylaminofluorene (AAF) plus partial hepatectomy (RH groups). Two additional Wistar rat groups received a second AAF treatment without (RH+AAF) and with a necrogenic dose of CCl4 (RH+AAF/CCl4) 15 d after selection. The number to liver ratio and volume of glutathione-s-transferase placental form-positive lesions were lower in the Wistar than the F344 RH groups 9 and 32 wk after initiation and increased after a second AAF cycle treatment with and without CCl4. DNA synthesis in glutathione-s-transferase placental form-positive lesions was low in Wistar RH group at 9 wk and was stimulated by additional AAF treatments. HCCs developed at 57-60 wk in F344 RH, Wistar RH+AAF, and RH+AAF/CCl4 rats. Tumor incidence and multiplicity were lower in RH+AAF rats than in RH+AAF/CCl4 and F344 rats. At 32 wk, PN exhibited c-myc overexpression that increased from RH to RH+AAF rats and to RH+AAF/CCl4 Wistar rats. This was associated with c-myc amplification in Wistar RH+AAF/CCl4 rats. These results showed correlation of c-myc overexpression and amplification with nodule propensity to progress to HCC in poorly susceptible Wistar rats and suggested a possible genetic mechanism for susceptibility to hepatocarcinogenesis. The experimental system used in this work may be a valuable tool for studies on molecular mechanisms underlying liver growth and tumorigenesis supported by c-myc overexpression.

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Section: Introductionmentioning

confidence: 99%

Correlation of c-myc overexpression and amplification with progression of preneoplastic liver lesions to malignancy in the poorly susceptible wistar rat strain

et al. 1999

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“…The process of carcinogenesis can be divided into at least 3 stages of initiation, promotion and progression (Farber and Sarma, 1987, Pitot et al, 1991. An anti-initiating cffect of DHEA has been suggested on the basis of thc in vitro cvidcncc of impaired carcinogen activation by the NADPH-dcpcndcnt mixcd function monooxygenasc system, consequent upon a decrease in G6PD activity (Schwartz and Perantoni, 1975;Feo et al, 1984Feo et al, , 1987.…”

mentioning

confidence: 99%

Inhibition by dehydroepiandrosterone of growth and progression of persistent liver nodules in experimental rat liver carcinogenesis

Simile

Pascale

Miglio

et al. 1995

Intl Journal of Cancer

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Dehydroepiandrosterone (DHEA) inhibits the development of early pre-neoplastic lesions and prevents tumor development in various tissues when given to animals during the initiation/promotion stages of carcinogenesis. Our purpose was to evaluate whether DHEA can also arrest the growth and progression of late lesions, such as persistent nodules (PNs) of rat liver. Male F344 rats were subjected to initiation by diethylnitrosamine followed by selection according to the "resistant hepatocyte" (RH) protocol. Fifteen weeks after initiation, when PNs were present in the liver, the rats were fed a diet with/without 0.6% DHEA for a maximum of 15 weeks. Glucose-6-phosphate dehydrogenase (G6PD) activity was 17- to 20-fold higher in PNs than in normal liver 15-30 weeks after initiation. It significantly decreased, in both liver and PNs, 16 hr after starting DHEA feeding. Further DHEA feeding for 3-15 weeks decreased G6PD activity by 55-58% in both tissues. Eight weeks after starting DHEA, a fall in the proportion of labeled cells, after continuous contact with 3H thymidine for 7 days, was found in nodules. Treatment for 15 weeks with DHEA caused a marked decrease in the number of nodules per liver, as well as in the incidence of PNs with diameters of 3-6 and > 6 mm, respectively, while it did not affect PNs with diameters < 3 mm. Nodules showing patterns of malignant transformation were present in 40% of rats not treated with DHEA, but not in DHEA-treated rats. All of 8 surviving rats not treated with DHEA had carcinomas at the 56th week, while only 1 out of 4 surviving rats treated with DHEA had carcinoma. These data indicate that DHEA inhibits G6PD activity in rat liver and in PNs in vivo. This is associated with growth restraint of PNs and results in inhibition of their progression to malignancy.

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Multiple mechanisms are responsible for altered expression of gap junction genes during oncogenesis in rat liver

Neveu

Hully

Babcock

et al. 1994

Journal of Cell Science

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Although several abnormalities in gap junction (GJ) structure and/or function have been described in neoplasms, the molecular mechanisms responsible for many of the alterations remain unknown. The identification of a family of GJ proteins, termed connexins, prompted this study of connexin32 (Cx32), connexin26 (Cx26) and connexin43 (Cx43) expression during rat hepatocarcinogenesis. Using antibody, cDNA and cRNA probes, we investigated connexin mRNA and protein expression in preneoplastic and neoplastic rat livers. In normal liver, Cx32 is expressed in hepatocytes throughout the hepatic acinus, Cx26 is restricted to periportal hepatocytes, and Cx43 is expressed by mesothelial cells forming Glisson's capsule. Most preneoplastic altered hepatic foci generated by diethylnitrosamine (DEN) initiation and either phenobarbital (PB) or 2,3,7,8-dichlorodibenzo-p-dioxin (TCDD) promotion exhibited decreased Cx32 or increased Cx26 staining. Foci from either protocol failed to display Cx43 immunoreactivity. In the majority of PB-promoted foci, Cx32 immunoreactivity decreased independently of changes in mRNA abundance. Continuous thymidine labeling, following cessation of PB promotion, showed that downregulation of Cx32 staining is reversible in foci that are promoter-dependent for growth, but irreversible in lesions that are promoter-independent for growth. Hepatic neoplasms from rats initiated with DEN and promoted with PB or TCDD also displayed modified connexin expression. While all 24 neoplasms studied were deficient in normal punctate Cx32 and Cx26 staining, altered cellular localization of these proteins was apparent in some tumors. Immunoblotting of crude tissue extracts revealed that neoplasms with disordered Cx32 staining showed immunoreactive bands with altered electrophoretic mobility. These observations show that hepatomas may downregulate Cx32 expression through changes in the primary structure of Cx32 or by post-translational modifications. Northern blotting of total tumor mRNAs failed to demonstrate consistent changes in the abundance of Cx32, Cx26 or Cx43 transcripts. Some tumors expressed steady-state transcripts without observable immunoreactivity, indicating that some hepatomas downregulate connexin immunoreactivity independently of mRNA abundance. Increased levels of Cx43 mRNA and protein were found in several neoplasms, but immunostaining was always localized to nonparenchymal cells. Areas of bile duct proliferation and cholangiomas displayed Cx43 staining, whereas, cholangiocarcinomas were deficient in immunoreactivity. These findings show that alterations in the expression of connexins, by either downregulation or differential induction, represent common modifications during hepatocarcinogenesis. Although our results imply that connexins represent useful markers for the boundary between tumor promotion and progression, preneoplastic and neoplastic rat hepatocytes fail to use a common mechanism to modify connexin expression.

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Gene Activation and Deactivation during Multistage Hepatocarcinogenesis in the Rat

Cited by 3 publications

References 59 publications

Correlation of c-myc overexpression and amplification with progression of preneoplastic liver lesions to malignancy in the poorly susceptible wistar rat strain

Correlation of c-myc overexpression and amplification with progression of preneoplastic liver lesions to malignancy in the poorly susceptible wistar rat strain

Inhibition by dehydroepiandrosterone of growth and progression of persistent liver nodules in experimental rat liver carcinogenesis

Multiple mechanisms are responsible for altered expression of gap junction genes during oncogenesis in rat liver

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