Effect of Claudin Expression on Paracellular Permeability, Migration and Invasion of Colonic Cancer Cells

Abstract

Tight junctions (TJs), the most apical intercellular structures in epithelial and endothelial cells, create a physiological intercellular barrier separating the apical and basolateral spaces, as well as regulating the paracellular permeability of various solutes. They also act as a divide between the apical and basolateral membranes, thereby maintaining cell polarity. TJs contain transmembrane proteins such as claudins, occludin and junctional adhesion molecules. The C-terminal regions of these proteins interact with cytosolic proteins, such as zonula occludens (ZO)-1, -2 and -3, which are linked to the actin cytoskeleton and are potentially involved in signal transduction.1-6) Among these transmembrane proteins, the claudin family of proteins (claudin-1 to -24) play a major role in maintaining the intercellular barrier. 7,8) Given that a loss of TJ structure and function is frequently observed in epithelium-derived cancers, [9][10][11][12] TJs have attracted considerable attention in relation to this disease. The loss of TJ structure and function is thought to promote cancer cell proliferation by allowing constitutive accessibility of cancers to nutrients and growth factors. As TJs function as a barrier against cancer cell invasion, loss of TJ structure and function could also stimulate the metastasis of tumors. 11,[13][14][15] Alteration in the expression of the constituent proteins of TJs, in particular claudins, is frequently observed in tumors clinically isolated from various types of tissues, including colon, breast, pancreas, prostate, uterus and ovary. [9][10][11][12][16][17][18][19][20] It was initially believed that these alterations in expression affect cancer development only through the modulation of the barrier function of TJs. However, a number of recent studies suggest that the expression of certain claudins modulates the invasiveness and migration of cancer cells through various mechanisms.9,11) For example, we recently reported that overexpression of claudin-4 or claudin-2 causes a decrease or an increase, respectively, in the migration activity of gastric carcinoma (AGS) cells. 21,22) Studies from other groups have also shown that claudin overexpression (claudin-1, 3, 4, 5) can affect the invasiveness and migration of various types of cancer cells. 16,[23][24][25][26] Thus, an alteration in claudin expression appears to play a role in the progression of tumors, both by modulating the barrier function of TJs and by altering the migration and invasiveness of the cancer cells. However, the overall relationship between claudin expression and these cell functions have not been fully elucidated, partly due to the different types of cells and different cell culture conditions (i.e. cell density) used in the various studies. For example, although we showed that overexpression of claudin-4 decreases cell migration activity in AGS cells, other groups have reported that the overexpression stimulates cell invasion and migration in human ovarian cancer cells, 25) but inhibits the invasiveness of pancreatic...

Claudin-4 overexpression is associated with epigenetic derepression in gastric carcinoma

“…Our data also show that claudin-4 overexpression increases the barrier function of TJs in gastric cancer cells, results that are consistent with previous studies in colon cancer 44 and MDCK cells, 45 thus, suggesting that overexpression of claudin-4 might suppress gastric cancer progression by enhancing the barrier function of TJs as well as by inhibiting cell migration and invasion.…”

The impact of CLAUDIN-1 on follicular thyroid carcinoma aggressiveness

“…The molecular mechanism involved in the internalization of CLAUDIN-1 into subcellular or nuclear compartments is hypothesized to be regulated by post-translational modifications like phosphorylation (D'Souza et al 2005), mutations (Dhawan et al 2005) and/or promoter gene hypermethylation (Boireau et al 2007). The increase in nuclear CLAUDIN-1 expression during scratch induction could reflect enhanced migration in close proximity of the scratch, because it has been suggested that CLAUDIN proteins translocate from the cell surface to intracellular compartments at the site where cell migration occurs (Takehara et al 2009). In our cell models, CLAUDIN-1 is already localized in the cell nucleus and only shows an enriched nuclear expression around the scratch in FTC cell lines.…”

Cluster analysis of claudin‐1 and ‐4, E‐cadherin, and β‐catenin expression in colorectal cancers

“…Other researchers have described that claudin-1 or -4 proteins and mRNA levels were upregulated in colon cancer [11,[13][14][15]18]. In vitro, overexpression of claudin-1 and -4 specifically stimulates invasive activity of colon cancer cells with activation of matrix metalloproteinases [11,19]. Since such claudins are crucial components of tight junctions, alteration in their expression may affect cell proliferation, motility, and invasiveness in cancer cells in vitro, and in vivo loss of their expression contributes to a poorly differentiated phenotype as well as disease progression.…”