Connexins in colorectal cancer pathogenesis Solveig Sirnes 1,2 , Guro E. Lind 1,2 , Jarle Bruun 1,2 , Tone A. Fykerud 1,2 , Marc Mesnil 3 , Ragnhild A. Lothe 1,2 , Edgar Rivedal 1,2 , Matthias Kolberg 1,2 and Edward Leithe 1,2 1 Department of Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 2 Faculty of Medicine, Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway 3 STIM Laboratory, ERL7368-CNRS, University of Poitiers, Poitiers, France The connexins constitute a family of integral membrane proteins that form channels between adjacent cells. These channels are assembled in plasma membrane domains known as gap junctions and enable cells to directly exchange ions and small molecules. Intercellular communication via gap junctions plays important roles in regulating cell growth and differentiation and in maintaining tissue homeostasis. This type of cell communication is often impaired during cancer development, and sev- eral members of the connexin protein family have been shown to act as tumor suppressors. Emerging evidence suggests that the connexin protein family has important roles in colorectal cancer development. In the normal colonic epithelial tissue, three connexin isoforms, connexin 26 (Cx26), Cx32 and Cx43, have been shown to be expressed at the protein level. Colorectal can- cer development is associated with loss of connexin expression or relocalization of connexins from the plasma membrane to intracellular compartments. Downregulation of connexins in colorectal carcinomas at the transcriptional level involves cancer- specific promoter hypermethylation. Recent studies suggest that Cx43 may constrain growth of colon cancer cells by interfer- ing with the Wnt/b-catenin pathway. There is also increasing evidence that the connexins may have potential as prognostic markers in colorectal cancer. This review discusses the role of connexins in colorectal cancer pathogenesis, as well as their potential as prognostic markers and targets in the prevention and treatment of the disease. Colorectal cancer is the third most common type of cancer worldwide, and more than 1.2 million people are diagnosed with the disease each year. 1 The incidence of colorectal can- cer is substantially higher in industrialized countries than in developing countries, indicating that the disease is strongly affected by lifestyle and environmental factors. Several risk factors have been associated with the disease, including genetics, obesity, high-fat diet, tobacco, alcohol and lack of physical activity. 2,3 Development of colorectal cancer is a multistep process. 4 Despite considerable progress in identify- ing the genetic and epigenetic changes associated with colo- rectal cancer development, the molecular biology underlying the clinically distinct subsets of the disease is still incom- pletely understood. 3 An increasing body of experimental evi- dence indicates that the connexin gene family may have important roles in colorectal cancer pathogenesis. In this review, we summarize the current knowledge on the role of the connexins in colorectal cancer. We also discuss the potential for connexins as prognostic markers and as targets in the prevention and treatment of the disease. Molecular Pathways in Colorectal Cancer The intestine can be anatomically divided into the small intestine and the large intestine, and the large intestine is fur- ther subdivided into the cecum, colon and rectum. 5 The wall of the intestine is composed of three tissue layers: the outer layer consists of several sheets of smooth muscle, the luminal surface consists of a single layer of epithelial cells, termed the mucosa, and the space between the outer muscle and the inner epithelial layer consists of connective tissue (stroma). The mucosa is responsible for the processing and absorption of nutrients and forms numerous invaginations into the underlying connective tissue, called crypts. Four types of dif- ferentiated intestinal epithelial cells mediate the various Key words: colorectal cancer, connexins, gap junctions, intercellular communication, prognostic markers, bystander effect, b-catenin, Wnt pathway Abbreviations: APC: adenomatous polyposis coli; CIMP: CpG island methylator phenotype; CIN: chromosomal instability; CK1: casein kinase 1; Cx: connexin; Dvl: dishevelled; GLA: gamma-lino- lenic acid; GSK3b: glycogen synthase kinase 3b; HGF/SF: hepato- cyte growth factor/scatter factor; LRP5/6: low-density lipoprotein receptor-related protein 5/6; MSI: microsatellite instability; TCF/ LEF: T-cell factor/lymphoid enhancer family; TK-HSV: thymidine kinase-herpes simplex virus Grant sponsor: Research Council of Norway through its Centres of Excellence funding scheme; Grant number: 179571; Grant sponsor: Norwegian Cancer Society; Grant number: 709125; Grant sponsor: South-Eastern Norway Health Authority; Grant number: 2010017 DOI: 10.1002/ijc.28911 History: Received 16 Jan 2014; Accepted 11 Mar 2014; Online 18 Apr 2014 Correspondence to: Edward Leithe, Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, P.B. 4950 Nydalen, NO-0424 Oslo, Norway, Tel.: 147-22-78-17-37, Fax: 147-22-78-17-45, E-mail: eleithe@rr-research.no Mini Review Int. J. Cancer: 00, 00–00 (2014) V C 2014 UICC International Journal of Cancer IJC