Role of connexins, pannexins and their channels in liver cancer

Direct intercellular communication mediated by connexin (Cx)-based gap junctions, consisting of 2 Cx hemichannels of adjacent cells, is a crucial goalkeeper of hepatic homeostasis. On the other hand, Cx hemichannels mediate paracrine communication, which has been implicated in various liver pathologies. Similarly, pannexin (Panx) channels have been identified as pathological pores.
The aim of this doctoral project was to characterize the role of Cxs, Panxs and their channels in liver cancer. Specific focus was put on the most common form of liver cancer namely, hepatocellular carcinoma (HCC), which often develops from chronic liver disease. Risk factors for the development of HCC include alcohol abuse, diabetes, viral hepatitis, but also exposure to carcinogenic chemicals. Carcinogenic chemicals can elicit their effect through non-genotoxic
(NGTX) mechanisms or genotoxic (GTX) mechanisms. The first study within this doctoral project revolved around the role of Cx hemichannel and gap junction functionality in NGTX and GTX carcinogenicity. It was found that Cx32 protein expression was downregulated by both NGTX and GTX chemicals in human hepatoma HepaRG cells. The second study addressed the expression of
Cxs and the functionality of gap junctions in HCC cell lines. Cx43 messenger ribonucleic acid (mRNA) and protein expression was upregulated at the expense of Cx26 in HCC. Gap junction functionality was minimal in almost all HCC cell lines. The third and final study characterized the expression of Cxs and Panxs in liver biopsies from patients suffering with various liver diseases, including liver cancer. It was found that Panx1 protein levels correlated with both Cx32 and Cx43 protein quantities. Furthermore, Panx1 gene expression was positively correlated with Panx2 gene expression. Most importantly, Panx3 proteins were detected in most liver biopsies.
Collectively these results showed that Cx and/or Panx expression display different levels of expression depending on the model and experimental set-up. This is probably indicative of a varying expression and functionality within the hepatocarcinogenesis process.