Hepatic gap junctions in the hepatocarcinogen-resistant DRH rat

Abstract

Although the gap junction or connexin (Cx) is considered to be a tumor-suppressor, it is also required for tumor promotion. Therefore, we examined hepatic gap junctions in hepatocarcinogen-resistant (DRH) rats. Specifically, we investigated gap junction structure and Cx32 expression during normal conditions and in response to a hepatocarcinogen, 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB). On a basal diet without 3'-MeDAB, hepatic gap junctions and Cx32 protein expression were greater in DRH rats than in control Donryu rats, as evidenced by morphometry, immunohistochemistry and immunoblotting. On a diet containing 3'-MeDAB, gap junctions and expressed Cx32 were increased significantly in Donryu rats, but not in DRH rats. In this condition, Donryu rats lost weight but DRH rats increased relative liver weight. After 3'-MeDAB treatment, cathepsin D expression in hepatocytes was significantly increased only in Donryu rats, indicating that DRH rats were less susceptible to 3'-MeDAB. The abundance of mitogen-activated protein kinase, some constituent of which might be associated with the degree of Cx protein phosphorylation, was reduced to a greater extent in Donryu than in DRH rats after 3'-MeDAB treatment. The resistance of DRH rats to carcinogenesis may be due partially to their stabilized gap junctions, which could coordinate metabolic coupling to evade 3'-MeDAB toxicity.

All-trans retinoic acid arrests cell cycle in leukemic bone marrow stromal cells by increasing intercellular communication through connexin 43-mediated gap junction

“…In a previous study from this laboratory [ 18 ], we demonstrated that GJIC function is dysfunctional between leukemic BMSCs. Such a finding is consistent with the reported decrease in GJIC in several solid tumors [ 8 , 38 , 39 ]. In the current study, we showed that GJIC between leukemic BMSCs is enhanced by ATRA treatment.…”

Connexin-based signaling and drug-induced hepatotoxicity

“…In this light, Cx32 -/- mice display lack of promotion of hepatocarcinogenesis by PB [121-123] and Wy-14,643 [143], suggesting that Cx32 signaling aggravates the adverse outcome. However, most evidence points to a rather defensive function for connexin signaling [90,144-149]. Thus, a high incidence of chemical-induced liver tumors was observed in mice deficient for Cx32 [90,144] and APAP-related liver injury is increased in Cx43 +/- mice [99].…”

State-of-the-art technologies, current opinions and developments, and novel findings: news from the field of histochemistry and cell biology

“…The authors suggested that the "drug"-induced accelerated diVerentiation of hepatic progenitor cells might serve as a possible treatment modality for several liver diseases. Hepatic gap junctions have been reported to be involved in hepatic carcinoma pathogenesis (see Gotow et al 2008). Rats of the DRH stain are resistant to the development of hepatocellular carcinoma.…”

“…Rats of the DRH stain are resistant to the development of hepatocellular carcinoma. Gotow et al (2008) investigated gap junction structure and Connexin32 (Cx32) expression under normal conditions and in response to a hepatocarcinogen (3Ј-methyl-4-dimethylaminoazobenzene (3ЈMeDAB). Using light and electron microscopy, freeze fractured replica electron microscopy, confocal laser scanning microscopy, immunoblotting and RT-PCR, the authors succeeded in documenting that, on a basal diet, hepatic gap junctions and Cx32 protein expression were greater in DRH rats than in control Donryu rats.…”