Wang L, Liu T, Wang Y, Cao L, Nishioka M, Aguirre RL, Ishikawa A, Geng L, Okada NAltered expression of desmocollin 3, desmoglein 3, and β-catenin in oral squamous cell carcinoma: correlation with lymph node metastasis and cell proliferation. Virchows Arch 451(5): 959-966
Desmocollin 3 (Dsc3) and desmoglein 3 (Dsg3) are both transmembrane glycoproteins that belong to the cadherin family of calcium-dependent cell adhesion molecules. beta-Catenin is a member of the cadherin-catenin complex that mediates homotypic cell-cell adhesion and is also an important molecule in the wnt signaling pathway. In this study, we examined the simultaneous expression level of Dsc3, Dsg3, and beta-catenin in oral squamous cell carcinomas (OSCCs) and normal oral epithelia using immunohistochemistry. There was a significant correlation (p < 0.05) among the following variables in OSCCs: reduced or loss of expression of Dsc3, Dsg3, and beta-catenin compared to normal oral epithelium, reduced or loss of expression of Dsc3 and histological grade (moderately or poorly differentiated), and reduced or loss of expression of beta-catenin and lymph node metastasis. Furthermore, a positive correlation was found between reduced or loss of beta-catenin staining and reduced or loss of Dsc3 staining in lymph node metastatic cancer tissue (r = 0.734, p < 0.05). These results suggest an abnormal expression of Dsc3, Dsg3, and beta-catenin induced in the progression of oral carcinomas and that the Dsc3 expression level might be related to the regulation of beta-catenin in lymph node metastasis and cell proliferation in OSCCs.
Available from: Jun-Xing Chen
- "Desmocollin 3 (DSC3), a member of cadherin superfamily, contributes to desmosome mediated cell-cell adhesion. Recent studies have observed loss of DSC3 in several cancer types, such as lymph node metastases of oral squamous cell carcinoma, breast cancer and colorectal cancer, where the decreased levels associated with cancer progression were regulated by epigenetic modification, , . However, little is known about the expression and regulatory mechanisms of DSC3 in prostate cancer. "
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ABSTRACT: Desmocollin 3 (DSC3), a member of the cadherin gene superfamily, is associated with pathogenesis of some cancers, but its role in prostate cancer (PCa) remains largely unknown.
DSC3 gene expression level in available PCa microarray dataset was examined using the Oncomine database. DSC3 transcript expression in prostate cell line panel and an independent tissue cohort (n = 52) was estimated by quantitative PCR (Q-PCR). Epigenetic status of DSC3 gene promoter in PCa was investigated by uploading three dataset (ENCODE Infinium 450K array data and two methylation sequencing) in UCSC genome browser. While pyrosequencing analysis measured promoter DNA methylation, Q-PCR estimates were obtained for DSC3 transcript re-expression after 5-Aza-deoxycytidine (5-Aza) treatment. Clinical relevance of DSC3 expression was studied by Kaplan-Meier survival analysis. Finally, functional studies monitoring cell proliferation, migration and invasion were performed in prostate cell lines after siRNA mediated DSC3 knockdown or following 5-Aza induced re-expression. EMT markers Vimentin and E-cadherin expression was measured by Western Blot.
Microarray data analyses revealed a significant decrease in DSC3 transcript expression in PCa, compared to benign samples. Q-PCR analysis of an independent cohort revealed DSC3 transcript down-regulation, both in PCa cell lines and tumor tissues but not in their benign counterpart. Examination of available NGS and Infinium data identified a role for epigenetic regulation DSC3 mRNA reduction in PCa. Pyrosequencing confirmed the increased DSC3 promoter methylation in cancer cell lines and restoration of transcript expression upon 5-Aza treatment further corroborated this epigenetic silencing mechanism. Importantly Kaplan-Meier analysis of an outcome cohort showed an association between loss of DSC3 expression and significantly increased risk of biochemical recurrence. Functional studies indicate a role for epithelial-mesenchymal transition in DSC3 regulated cell migration/invasion.
Taken together, our data suggests that DNA methylation contributes to down-regulation of DSC3 in prostate cancer, and loss of DSC3 predicts poor clinical outcome.
Available from: Wang-Kai Fang
- "Down-regulation of desmosomal proteins has been suggested to be a sign of reduced adhesiveness in metastasizing cells (Green et al., 2007). However, all prior studies in cancer report contradictory results (Kurzen et al., 2003; Yashiro et al., 2006; Chen et al., 2007; Wang et al., 2007; Brennan et al., 2009; Teh et al., 2011). We demonstrate in here that DSG3 may be involved in the progression of ESCC and serve as a prognostic marker; while the expression of DSG2 cannot be used as a predictor for ESCC patient outcomes. "
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Desmogleins (DSGs) are major members among the desmosomal cadherins critically involved in cell-cell adhesion and the maintenance of normal tissue architecture in epithelia. Reports exploring links of DSG family member expression with cancers are few and vary. The aim of this study was to investigate the ratio of DSG2 and DSG3 mRNA expression in esophageal squamous cell carcinoma (ESCC) tissue to normal tissue (T/N ratio) and evaluate correlations with clinical parameters.
The mRNA expression of DSGs, as well as γ-catenin and desmoplakin, was detected by real-time quantitative RT-PCR in 85 cases of ESCC tissue specimens.
The expression level of DSG3 mRNA was significantly higher than that of DSG2 in ESCC specimens (p = 0.000). DSG3 mRNA expression highly correlated with histological grade (p = 0.009), whereas that of DSG2 did not significantly relate to any clinicopathologic parameter. Kaplan-Meier survival analysis showed that only DSG3 expression had an impact on the survival curve, with negative DSG3 expression indicating worse survival (p = 0.038). Multivariate Cox regression analysis demonstrated DSG3 to be an independent prognostic factor for survival. Furthermore, correlation analysis demonstrated the mRNA level of DSG3 to highly correlate with those of γ-catenin and desmoplakin in ESCC samples (p=0.000), implying that the expression of desmosomal components might be regulated by the same upstream regulatory molecules.
Our findings suggest that DSG3 may be involved in the progression of ESCC and serve as a prognostic marker, while expression of DSG2 cannot be used as a predictor of ESCC patient outcome.
Available from: Felipe Andrés Cordero da Luz
- "Lo Muzzio et al. (1999)  demonstrated that the absence of β-and γ-catenin was considered to be a hallmark of aggressive biological behavior, independent of differentiation grade. Using univariate analysis, an inversely significant association between the absence or reduction of β-catenin and histological grading of malignancy, tumor invasion and metastases        has been identified, although no significant correlation between its expression and aspects of nodal metastases such as the number of affected lymph nodes and the presence of extracapsular metastases could be found . Interestingly, in contrast with these findings, Yu et al. (2005)  showed that the high expression of β-catenin is related to nodal metastasis. "
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