Sequential Down-regulation of E-Cadherin with Squamous Cell Carcinoma Progression: Loss of E-Cadherin via a Prostaglandin E2-EP2–Dependent Posttranslational Mechanism

Abstract

The incidence of skin cancer is on the rise, with over 1 million new cases yearly. Although it is known that squamous cell cancers (SCC) are caused by UV light, the mechanism(s) involved remains poorly understood. In vitro studies with epithelial cells or reports examining malignant skin lesions suggest that loss of E-cadherin-mediated cell-cell contacts may contribute to SCCs. Other studies show a pivotal role for cyclooxygenase-dependent prostaglandin E 2 (PGE 2 ) synthesis in this process. Using chronically UV-irradiated SKH-1 mice, we show a sequential loss of E-cadherin-mediated cell-cell contacts as lesions progress from dysplasia to SCCs. This E-cadherin down-regulation was also evident after acute UV exposure in vivo. In both chronic and acute UV injury, E-cadherin levels declined at a time when epidermal PGE 2 synthesis was enhanced. Inhibition of PGE 2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo abrogated this UV-induced E-cadherin downregulation. In contrast, addition of PGE 2 or the EP2 receptor agonist butaprost to PMK produced a dose-and timedependent decrease in E-cadherin. We also show that UV irradiation, via the PGE 2 -EP2 signaling pathway, may initiate tumorigenesis in keratinocytes by down-regulating Ecadherin-mediated cell-cell contacts through its mobilization away from the cell membrane, internalization into the cytoplasm, and shuttling through the lysosome and proteasome degradation pathways. Further understanding of how UV-PGE 2 -EP2 down-regulates E-cadherin may lead to novel chemopreventative strategies for the treatment of skin and other epithelial cancers. [Cancer Res 2007;67(16):7654-64]

Prostaglandin Gβγ signaling stimulates gastrulation movements by limiting cell adhesion through Snai1a stabilization

“…Recent work in cell culture has shown that chemical or antisense interference with the prostaglandin signaling pathway components results in decreased Snai1 transcription and increased E-cadherin protein levels (Dohadwala et al, 2006;Brouxhon et al, 2007). However, our qRT-PCR and whole-mount ISH analyses showed that snai1a and snai1b levels were not significantly different in ptges versus control morphants ( Fig.…”

Host knockout of E-prostanoid 2 receptors reduces tumor growth and causes major alterations of gene expression in prostaglandin E2-producing tumors

“…In the present study, several hundreds of genes showed changed expression in the tumor tissues from the EP2-knockout mice compared with tumor tissues from the wild-type mice. A reason for this could be that EP2 signaling in host tissues is involved in several different pathways that are important events in tumor cells associated with tumor progression, including angiogenesis, the upregulation of COX-2, the loss of E-cadherin expression and anti-apoptosis in stem cells (16,22,(25)(26)(27)(28). Prom-1, also known as CD133, and CD44 are well-known markers of cancer stem cells, indicating reduced gene expression in the tumor tissues from the EP2-knockout mice in the present study.…”

Ectodomain-Specific E-Cadherin Antibody Suppresses Skin SCC Growth and Reduces Tumor Grade: A Multitargeted Therapy Modulating RTKs and the PTEN–p53–MDM2 Axis

“…Mice bearing tumors, with an estimated volume of 100 mm 3 were subsequently randomized to receive a one-time injection of saline (n ¼ 6), IgG (10 mg/kg, n ¼ 6), or anti-sEcad mAb (10 mg/kg, n ¼ 7) and tumor growth was monitored for an additional 20 days. Starting from 12 days, anti-sEcad treatment demonstrated a significant decrease in tumor volume and burden compared with controls ( Fig.…”

“…Although the best known function of PTEN involves the dephosphorylation of PtdIns (3,4,5)P3 at the plasma membrane surface, cytoplasmic PTEN has been shown to inhibit cell proliferation (38). Moreover, nuclear PTEN has been proposed to regulate the cell cycle through the suppression of cyclin D1 activity (49).…”

“…E-cadherin belongs to a family of integral transmembrane glycoproteins that promote the establishment of calcium-dependent homotypic cell-cell adhesions. Using a chronic photocarcinogenesis model, we have previously demonstrated a sequential ultraviolet (UV)-induced loss of membrane-bound E-cadherin with progression from normal epithelium to dysplastic lesions, papillomas, and overt SCCs (3). Moreover, we have found a concomitant increase in E-cadherin mRNA and a progressive increase in the shedding of the E-cadherin extracellular domain fragment (termed sEcad), suggesting that posttranslational processing of E-cadherin via ectodomain shedding plays an important role in UV-induced skin carcinogenesis (4).…”