Role of Cadherinin physiologicalandpathological processes

E-cadherin expression is regulated in both physiological and pathological processes, such as embryonic morphogenesis and tumorigenesis. Tissue and organ formation is regulated in a spatio-temporal manner involving cell proliferation, death, cell-cell adhesion, cell-substrate adhesion, polarization, and migration. One example of this highly regulated process is blas-tocyst differentiation. E-Cadherin has an essential function in the formation of the blastocyst during mouse embryonic development. Another example of the normal physiological processes associated with E-cadherin regulation is the formation of fluid space in development of murine cochlea. In this embryonic process, E-cadherin is downregulated on the lateral membranes of reticular lamina. This down-regulation allows the process of fluid space opening in the organ of Corti. Wound healing is a third example where a physiological event involves regulation of E-cadherin expression. Injury of the epithelial cell layer in the skin signals the release of cytokines and other factors, such as epidermal growth factor (EGF). These signals reduce cell adhesion and stimulate cell motility, allowing for wound re pair. Subsequent to wound repair, cell adhesion is upregulated to restore the epithelial layer to its normal physiological state. Therefore, E-cadherin has to be highly regulated in the above normal physiological processes. Conversely, aberrant growth and differentiation result when E-cadherin is not tightly regulated, such as in cancer.

Association of E-cadherin with neighboring cells acts to inhibit cell mobility and to maintain normal epithelial cell phenotype. Tumorigenesis is an example of a pathological process that involves E-cadherin regulation. The loss or down-regulation of E-cadherin expression has been described in several tumors including stomach (Shino 1995; Tamura, 2000), colon (Van Aken, 1993; Dorudi, 1993), pancreas (Pignatelli, 1994), liver (Joo, 2002), prostate (Morton et al., 1993; Umbas et al., 1994; Ross et al., 1994; Bussemakers et al, 1994; Pan et al., 1998; Noe et al., 1999; Cheng et al., 1996), breast (Lim and Lee, 2002; Hiraguri et al, 1998; Moll et al., 1993; Palacios et al., 1995; Gamallo et al., 1993; Oka et al., 1993; Rasbridge et al., 1993; De Leeuw et al., 1997), uterus (Sakuragi et al., 1994), ovary (Veatch et al., 1994), thyroid (Brabant et al., 1993), and head and neck (Mattijssen et al., 1993). Recent reports suggest that poorly differentiated tumors exhibit reduced E-cadherin expression as a consequence of down-regulation or defects in catenins (Kadowaki et al., 1994; Kawa-nishi et al., 1995; Navarro et al., 1993; Oyama et al., 1994). Therefore, the results from these studies suggest that the degree of differentiation of tumors is related to the level of E-cadherin expression.

E-cadherin acts as an inhibitor of the invasive and metastatic phenotype of cancer cells. Since tumor invasion and metastasis is a multistep process, E-caderin may play a significant role in regulating invasion and metastasis at the initial steps in the process by promoting ho-motypic cell-cell adhesion. Numerous mechanisms affecting E-cadheirn-catenin complex formation are associated with a reduction in cell adhesion. While gene mutation is responsible for inactivating E-cadherin-mediated cell adhesion in some breast cancers and gastric ad-enocarcinomas (Berx et al., 1998a; Berx et al., 1998b), the exact mechanism of E-cadherin down-regulation in other highly invasive tumors is still under investigation. Mechanisms that regulate homophilic cell adhesion include reduction or loss of E-cadherin expression, reduced transcription of genes encoding catenin proteins, redistribution of E-cadherin to different sites within the cell, shedding of E-cadherin, cleavage of E-cadherin, and competition of proteins for binding sites on E-cadherin (Cavallaro and Christofori, 2004).

The proximal E-cadherin promoter contains multiple regulatory elements including three E-boxes, a single CCAAT box, and a GC-rich element. Therefore, the E-cadherin promoter contains more than one site for transcription factors to bind and regulate gene transcription in cancers. These factors include AP-2 (Batsche et al., 1998), SNAIL (Battle et al., 2000), SLUG (Hajra et al., 2002), dEF1/ZEB-1 (Grooteclaes and Frisch, 2000), SIP1/ZEB-2 (Comijn et al., 2001), E12/E47 (Perez-Moreno et al., 2001), and LEF/TCF (Huber et al., 1996). While the retinoblastoma gene and c-myc protooncogene products transactivate the E-cadherin promoter in epithelial cells through interaction with AP-2 transcription factors (Batsche et al., 1998), transcription of E-cadherin is down-regulated by overexpression of ErbB2 (D'Souza and Taylor-Papadimitriou, 1994). SNAIL and SLUG transcription factors have been shown to repress E-cadherin expression in breast cancer cell lines via all three

E-box elements, but particularly, via EboxA and EboxC, located in the proximal E-cadher-in promoter (Hajra et al., 2002). Moreover, SLUG is a putative in vivo repressor of E-cad-herin in breast cancer (Hajra et al., 2002). The E-cadherin promoter also contains binding sites for the lymphoid enhancer factor 1 (LEF1)-ß-catenin transcription factor complex; this complex down-regulates E-cadherin expression (Huber et al., 1998). Overexpression of in-tegrin-linked protein kinase (p59ilk) stimulates LEF1-ß-catenin signaling and causes down-regulation of E-cadherin expression with a concomitant decrease in cell adhesion (Novak et al., 1998). A single nucleotide polymorphism in the E-cadherin promoter has also been associated with a higher risk of prostate cancer in certain ethnic populations with a possible role in transcriptional regulation of E-cadherin gene expression in these individuals (Goto et al., 2007).

Gene transcription can also be regulated by epigenetic inactivation. Many cancer cells have been shown to use this mechanism to inactivate tumor-suppressor genes (Sidransky, 2002). Methylation of genes that encode p16 (cyclin-dependent kinase inhibitor), DAPK (death-associated protein kinase, apoptosis associated protein), and MGMT (a DNA repair protein, methyl O-guanine methyltransferase) has been implicated in lung, and head and neck cancer (Esteller et al., 1999; Sanchez-Cespedes et al., 2000). Aberrant methylation of the hMLH1 promoter has also been associated with microsatellite instability in colon cancer (Grady et al., 2001). Methylation of APC (Usadel et al., 2002), a key component in Wnt-ß-catenin signaling, is associated with early-stage lung cancer and esophageal cancer (Kawakami, 2000). E-cadherin expression is downregulated in highly invasive prostate tumors as a result of transcriptional regulation (Morton et al., 1993; Kuczyk et al, 1998). Reduction in E-cadherin expression in prostate cancer cells has been attributed to hypermethylation of CpG islands in the E-cadherin gene promoter (Graff et al., 1995; Graff et al., 1997; Herman et al., 1996; Hirohashi, 1998; Li et al., 2001). This type of silencing of E-cadherin gene expression is also seen in cervical cancer cell lines and tumors (Chen et al., 2003). In summary, epigenetic inactivation of genes is an alternative mechanism used to regulate expression of certain genes in cancer cells. The significance and mechanism of gene inactivations associated with prostate cancer cell invasion remain to be determined.

Post-translational modification is an alternative mechanism to regulate E-cadherin-de-pendent homophilic cell adhesion (Hirohashi, 1998). Protein tyrosine kinases (PTKs) and phosphatases (PTPs), regulate intracellular phosphotyrosine levels, thereby regulating diverse cellular behaviors such as adhesion, growth and differentiation, and migration. Her2/Neu or ErbB2 tyrosine kinase, as well as transmembrane tyrosine phosphatases such as PTP||, PTPk, PTPA and LAR, have been found to be associated with cadherin-catenin complexes in epithelial cells, suggesting opposing roles for these proteins in regulating cadherin-catenin association (Hellberg et al., 2002). Stimulation of growth factor receptors, i.e. EGF receptor (EGFR), can also regulate E-cadherin expression in tumor cells in a post-translational manner (Hazan and Norton, 1998; Moustafa et al, 1999). A reciprocal and reversible control of intercellular adhesion and cell proliferation occurs with increased expression of EGFR in several epithelial tumors (Jawhari et al, 1999). Restoration of E-cad-

herin expression in human papilloma virus-transfected keratinocytes reversed the invasive phenotype and, interestingly, down-regulated EGFR expression (Wilding et al., 1996). An inverse relationship between EGFR activation and E-cadherin expression was also observed in lung cancer cells treated with neutralizing monoclonal antibody to EGFR (Mous-tafa et al., 1999). By blocking EGFR stimulation in lung cancer cells, E-cadherin expression is induced. Activation of Src can also induce tyrosine phosphorylation of E-cadherin and inhibit cell-cell adhesion. As a result of Src activation, the E-cadherin complex is ubiquiti-nated, leading to its endocytosis and thereby inhibiting homophilic cell adhesion (Fujita et al., 2002). Either transcriptional or post-translational modification of the cadherin-catenin complex can determine the integrity of the adherens junction, as well as regulating downstream signaling.

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