Abstract
Connexin-based channels play key roles in cellular communication and can be affected by deleterious chemicals. In this study, the effects of various genotoxic carcinogenic compounds, non-genotoxic carcinogenic compounds and non-carcinogenic compounds on the expression and functionality of connexin-based channels, both gap junctions and connexin hemichannels, were investigated in human hepatoma HepaRG cell cultures. Expression of connexin26, connexin32, and connexin43 was evaluated by means of real-time reverse transcription quantitative polymerase chain reaction analysis, immunoblot analysis and in situ immunostaining. Gap junction functionality was assessed via a scrape loading/dye transfer assay. Opening of connexin hemichannels was monitored by measuring extracellular release of adenosine triphosphate. It was found that both genotoxic and non-genotoxic carcinogenic compounds negatively affect connexin32 expression. However, no specific effects related to chemical type were observed at gap junction or connexin hemichannel functionality level.
Highlights
Gap junctions allow for direct intercellular communication between neighboring cells via diffusion of small and hydrophilic molecules and ions
Previous in vitro carcinogenicity testing has proven that HepaRG cells are better at distinguishing genotoxic carcinogenic (GTX) chemicals from non-genotoxic carcinogenic (NGTX) and NC chemicals via transcriptomics analysis than primary rat hepatocytes [32]
The results indicated that Cx26 and Cx32 are still being expressed in HepaRG cells, despite their tumorigenic origin (Figure 1)
Summary
Gap junctions allow for direct intercellular communication between neighboring cells via diffusion of small and hydrophilic molecules and ions. This flux, called gap junction intercellular communication (GJIC), is crucial for the preservation of normal homeostasis [1]. Gap junctions are built up by two connexin hemichannels of adjacent cells, which are each themselves constituted by six connexin (Cx) proteins. 21 mammalian connexin proteins have been discovered [11]. Because of their cell-specific expression, not all connexin proteins are found in the liver. During liver disease, including cancer, hepatic Cx43 expression increases at the expense of Cx32 and Cx26 [17,18,19,20,21]
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