Connexin 43, but not connexin 32, is mutated at advanced stages of human sporadic colon cancer

Abstract

The membrane-spanning connexin proteins form microscopic intercellular channels that directly connect the cytoplasms of adjacent cells and as such have been implicated in maintenance of tissue homeostasis. They are considered to act as tumor suppressors since their function or expression is frequently aberrant in tumor cells. Several mechanisms appear to be involved in this, but irreversible mutational alterations have not yet been proved to be among them. In this study we have demonstrated for the first time that connexin 43 but not connexin 32 is specifically and quite frequently mutated in human colon sporadic adenocarcinomas. All tumor-associated mutations led to a shift of reading frame and were located in the multifunctional carboxylterminal domain of the protein. Expression of mutated connexin 43 protein was restricted to invasive structures of tumors. These findings suggest that mutational alterations of connexin 43 are involved in advanced stages of progression of human colon cancer towards malignancy.

Pathological Implications of Cx43 Down-regulation in Human Colon Cancer

“…These frame-shift mutations result in the carboxyterminal domain truncated Cx43 expression, which is suggestive of the importance of CT-domain of Cx43 in growth regulation. The importance of Cx43 in colon cancer is evident from the studies indicating its frequent mutations and their correlation with the colon sporadic adenocarcinomas (Dubina et al, 2002). In fact, studies have shown that many proteins, involved in growth control interact with Cx43 at its CT domain (Giepmans, 2004).…”

Connexin43 is overexpressed in ApcMin/+‐mice adenomas and colocalises with COX‐2 in myofibroblasts

“…[1][2][3] Gap junctions are the only channels that allow direct exchange of small metabolites between cells. The building proteins of gap junction channels, connexins (Cx), constitute a family with as many as 20 distinct isoforms in mammals.…”

Expression of connexin 26 in endometrial adenocarcinoma--analysis of correlations with some anatomoclinical features.

“…Only one connexin gene mutation in human tumours has been described so far (advanced stages of human sporadic colon cancer) [26]. On the other hand, there is growing body of evidence suggesting that connexin genes could be inactivated by hypremethylation of their promoter regions [27].…”