Connexins in colorectal cancer pathogenesis

Abstract

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 several 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 cancer 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 cancerspecific promoter hypermethylation. Recent studies suggest that Cx43 may constrain growth of colon cancer cells by interfering 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.

Connexin 43 (Cx43) Expression in Laryngeal Squamous Cell Carcinomas: Preliminary Data on Its Possible Prognostic Role

“…As already known, the passage of small proteic molecules across GJs permits the exchanges between cytosol and extracellular space; moreover, the hemichannels of adjacent cells can directly connect their cytosol and transfer molecular signals from cell to cell, as bystander effect [3,7]. GJs play a physiological role either as regulators of homeostasis or as vehicles of apoptotic signaling regulators in tissue development and differentiation.…”

“…Lastly, a potential prognostic role of Connexins has been proposed in several cancers [7,17,18,22]: in colorectal adenocarcinomas, the loss of Cx43 expression in cancer cells has been linked with poor clinical outcome in I-II stages, suggesting a Cx43 prognostic role to identify a subgroup of high-risk patients, not submitted to chemo/ radioadjuvant therapy, for the standard guidelines [7]. Further studies could be performed to demonstrate the opportunity to submit to chemo/radioadjuvant therapy those patients with colorectal adenocarcinomas in I-II stages without Cx43 expression.…”

“…Its channel function depends on phosphorylation and dephosphorylation of the C-terminal domain, but recent evidence suggests its potential role as scaffold protein promoting the different assembly of the actin cytoskeleton and microtubules [4,6]. It seems that the C-terminal domain of Cx43 is responsible either for the tumor suppressor effect or the invasiveness, regulating also the epithelial-mesenchymal transition [7]; therefore the presence of two different activities of Cx43 protein has been proposed, one involving intercellular communication across communicating hemichannels and one acting as scaffold for cytoskeleton associated proteins [4]. Experimental data have shown the role of Cx43 in the control of cell proliferation and apoptosis for its ability to form hemichannels exchanging apoptotic and cell growth factors between extracellular and intracellular matrix, but also its role in promoting tumor progression and metastasis [7].…”

“…It seems that the C-terminal domain of Cx43 is responsible either for the tumor suppressor effect or the invasiveness, regulating also the epithelial-mesenchymal transition [7]; therefore the presence of two different activities of Cx43 protein has been proposed, one involving intercellular communication across communicating hemichannels and one acting as scaffold for cytoskeleton associated proteins [4]. Experimental data have shown the role of Cx43 in the control of cell proliferation and apoptosis for its ability to form hemichannels exchanging apoptotic and cell growth factors between extracellular and intracellular matrix, but also its role in promoting tumor progression and metastasis [7]. Recent reports suggest a more complex role of Cx43 in the different stages of tumor progression [4,7,8]; Cx43 downregulation has been associated with development of cancer phenotype [2,9], while aberrant Cx43 upregulation in advanced stages of carcinomas suggests the possibility that cancer cells may communicate with normal host cells across hemichannels, playing a role in migration and growth of metastatic cells.…”

“…Experimental data have shown the role of Cx43 in the control of cell proliferation and apoptosis for its ability to form hemichannels exchanging apoptotic and cell growth factors between extracellular and intracellular matrix, but also its role in promoting tumor progression and metastasis [7]. Recent reports suggest a more complex role of Cx43 in the different stages of tumor progression [4,7,8]; Cx43 downregulation has been associated with development of cancer phenotype [2,9], while aberrant Cx43 upregulation in advanced stages of carcinomas suggests the possibility that cancer cells may communicate with normal host cells across hemichannels, playing a role in migration and growth of metastatic cells. Aberrant Cx43 expression has been detected in advanced stages of prostatic and colonic adenocarcinomas [8,10], and metastatic cutaneous melanoma [11].…”