T-Cadherin Negatively Regulates the Proliferation of Cutaneous Squamous Carcinoma Cells

Abstract

T-cadherin is a unique member of the cadherin superfamily that lacks the transmembrane and cytoplasmic domains, and is instead linked to the cell membrane via a glycosyl-phosphatidylinositol anchor. We previously reported that T-cadherin was specifically expressed on the basal keratinocytes of the epidermis, and the expression of T-cadherin was significantly reduced in invasive cutaneous squamous cell carcinoma (SCC) and in the lesional skin of psoriasis vulgaris. In this study, to obtain an insight into the role of T-cadherin in keratinocytes, we used transfection methods and examined the effect of overexpression or knockdown of T-cadherin in immortalized keratinocyte cell lines derived from SCC. T-cadherin overexpressed cells showed clearly reduced cell proliferation, but the influence of cell-cell adhesiveness and cell mobility was not detected. Using a tetracycline-regulated expression system, we also confirmed that the suppression of cell proliferation was dependent on the expression level of T-cadherin. Cell cycle analysis demonstrated that over expression of T-cadherin induced a delay in the G(2)/M phase. Our findings suggest that T-cadherin acts as an endogenous negative regulator of keratinocyte proliferation and its inactivation is the cause for keratinocyte hyperproliferation in SCC or in psoriasis vulgaris.

Genetic and epigenetic inactivation of T‐cadherin in human hepatocellular carcinoma cells

“…In this study, we demonstrated that T-cadherin had antiproliferative effects and antitumorigenic roles in HCC cells. These findings were consistent with those of previous studies on other cancer cell types 5,26,27 and suggest that T-cadherin may have different and perhaps opposite roles in epithelial and endothelial cells. Although the antitumorigenic roles of T-cadherin have been documented in a number of human cancer cell types, 5,26,27 the molecular mechanisms are unclear.…”

“…The underexpression of T-cadherin in HCC cells might be attributed to frequent allelic losses, promoter hypermethylation and histone deacetylation. Similar to the antitumorigenic effects of T-cadherin in other human cancers, 5,6,27 T-cadherin was able to inhibit cell growth, enhance apoptosis and suppress tumorigenicity in HCC cells. This antitumorigenic effect may be due to the inhibitory ability of T-cadherin on JNK and c-Jun activities in HCC cells.…”

“…4a). Since previous studies have shown that T-cadherin induced G 2 /M arrest in gliomas and cutaneous squamous carcinoma, 26,27 we examined the cell cycle changes of T-cadherin-stable transfectants with flow cytometric analysis. After cell synchronization with serum-free treatment, we found that all T-cadherin transfectants of PLC/PRF/5 (C5 and C8) had higher proportions of cells at the G 2 /M phase than their vector controls (Fig.…”

Malignant Transformation in Skin is Associated with the Loss of T-Cadherin Expression in Human Keratinocytes and Heterogeneity in T-Cadherin Expression in Tumor Vasculature

“…Stimulation of vascular endothelial cells and Tcadherin overexpressing HEK293 cells with plasma low density lipoproteins demonstrated the T-cadherin-induced signaling involving phospholipase C and IP3 formation, intracellular Ca 2+ mobilization, activation of tyrosine kinases Erk 1/2, and nuclear translocation of NF-kB (Kipmen-Korgun et al, 2005;Rubina et al, 2005b). However, in contrast to endothelial cells, overexpression of T-cadherin in C6 glioma (Huang et al, 2003) hepatocellular carcinoma cells (Chan et al, 2008), in immortalized keratinocytes (Mukoyama et al, 2005) and in p53(-/-) mouse embryonic fibroblasts (Chan et al, 2008) suppresses proliferation by delaying the G 2 /M phase progression. In hepatocellular carcinoma cells T-cadherin expression also increases sensitivity to TNF-induced apoptosis (Chan et al, 2008).…”

BRN2 is a transcriptional repressor of CDH13 (T-cadherin) in melanoma cells

“…Loss of cell surface glycoprotein T-cadherin (H-cadherin, Cadherin-13, gene CDH13) has been implicated in the progression of various cancers. [1][2][3][4] A role for T-cadherin as a tumor suppressor was first proposed in a study aimed at identification of genes differentially expressed in human breast cancer cells: T-cadherin transcript was found to be undetectable in all examined breast cancer cell lines as well as in cell lines derived from a variety of other cancers including neuroblastoma, lymphoma, renal carcinoma, squamous cell carcinoma, colon carcinoma, small-cell lung carcinoma, hepatocarcinoma and melanoma. 4 In addition to a low frequency of CDH13 loss of heterozygosity due to deletion of chromosome 16q24, CDH13 promoter hypermethylation is a common phenomenon for inactivation of CDH13 in several malignancies.…”