Role of Connexin32 and beta-Catenin in Tumor Promotion in Mouse Liver

Abstract

Tumor promoters are nonmutagenic chemicals that increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. The molecular mechanisms underlying this process are only partly understood but interference with signaling pathways regulating cell division and/or cell death is likely to be important. Ras- and beta-Catenin-dependent signaling is important for both of these processes and ras and beta-catenin genes are known mutational targets in mouse hepatocarcinogenesis. About 80% of liver tumors generated in mice by a promotional regimen including phenobarbital (PB) as tumor promoter and N-nitrosodiethylamine (DEN) as initiator showed beta-catenin mutations whereas Ha-ras mutations were not detected. By contrast, tumors from mice treated with DEN alone showed a approximately 30% Ha-ras mutation prevalence but no beta-catenin mutations. This result suggests that PB-mediated promotion in mouse liver consists in a positive selection for hepatocytes harboring mutations in beta-catenin. The gap junction protein connexin 32 (Cx32) was also found to be involved in tumor promotion by PB because Cx32 gene knockout mice were almost entirely resistent to the promotional effects of the barbiturate. The link between beta-catenin-signaling and Cx32-dependent gap junctional intercellular communication, if existent, remains obscure.

Altered Tumor Biology and Tumorigenesis in Irradiated and Chemical Carcinogen-Treated Single and Combined Connexin32/p27Kip1-Deficient Mice

“…Increased murine hepatocarcinogenesis is often linked with MAPK pathway activation resulting from Ha-ras mutation (42,43). In these studies, we did not detect any correlation between Cx32/p27 genotype and the frequency of liver tumors harboring activating Ha-ras codon-61 mutations nor did we detect any β-catenin exon 2 or 3 codon mutations, insertions or deletions.…”

Connexins, E-cadherin, Claudin-7 and β-catenin transiently form junctional nexuses during the post-natal mammary gland development

“…Using an immunoprecipitation assay, we first demonstrated that Cx32 interacts with E-cadherin and β-catenin at both tested time point. Although Cx32 co-localization and co-regulation with E-cadherin and β-catenin have been observed in other tissues (Schwarz, Wanke et al 2003) (Kanczuga-Koda, Wincewicz et al 2014) (Ionta, Rosa et al 2012) (Plante, Cyr et al 2005) (Plante, Charbonneau et al 2006), to our knowledge, this is the first report of their physical interaction.…”

Altered Expression and Localization of Connexin32 in Human and Murine Gastric Carcinogenesis

“…In human lung cancer, a concurrent reduction in E-cadherin and Cx43 expression is significantly associated with differentiation and progression, and exogenous expression of Cx43 in human pulmonary carcinoma cells significantly induces E-cadherin expression [32]. On the basis of results obtained using Cx32-null mice treated with Nnitrosodimethylamine and phenobarbital, Schwarz et al [33] suggested that the loss of Cx32 function and mutation of b-catenin were important during hepatocarcinogenesis.…”