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Purpose: Non-muscle invasive bladder cancer (NMIBC) is a highly recurrent disease that progresses to muscle-invasive bladder cancer (MIBC) in 5–25% of the cases. Epithelial-mesenchymal transition (EMT) has been associated with features of disease progression. Thus, we aimed to characterize the cadherin switch (CS), an EMT hallmark, and its regulatory mechanisms in bladder cancer (BlCa) progression, as well as the biological role of RCAD, a lesser-known cadherin, in bladder carcinogenesis. Methods: Cadherin mRNA and promoter methylation levels were retrieved from The Cancer Genome Atlas (TCGA). Validation was performed in an independent set of 121 primary BlCa (NMIBC and MIBC) and 40 normal bladder samples from IPO Porto, using RT-qPCR and qMSP. Immunohistochemistry was performed in these samples and in 14 additional sarcomatoid BlCa. CRISPR-Cas9 was performed to explore the potential in vitro impact of RCAD on BlCa cell migration and invasion. Results: In both the TCGA and IPO Porto BlCa cohorts, cadherin gene deregulation was observed compared to normal tissue samples, independent of promoter methylation. At the protein level, decreased E-cadherin and increased P- and R-cadherin expression was noted in BlCa tissues. In sarcomatoid BlCa the same trend was observed, with a more intense staining compared to that in conventional MIBCs. RCAD knockout considerably reduced the malignant properties of BlCa cells. Conclusions: Our data indicate that E-, P- and R-cadherin switches occur in BlCa, being associated with tumor progression. Promoter methylation is not the likely mechanism underlying cadherin expression deregulation. Our findings suggest an oncogenic role of RCAD in BlCa progression. [ABSTRACT FROM AUTHOR]

Background: Oral cancer progression is a multi-step process in which adhesion molecules play a pivotal role in the development of recurrent, invasive, and distant metastasis. The aim of this study was to adopt prognostic biomarkers to assess the lymph node metastasis of OSCC that will facilitate in deciding the treatment modality by the surgeons. Objectives: The objectives of the study were to assess the biological behaviour of OSCC by correlating the expression levels of P-Cadherin and WNT5A immunohistochemically. Methods: A total of 60 selected OSCCs cases (lymph node metastasis n = 30, non-metastatic n = 30) and 10 normal healthy controls were quantitatively and qualitatively analysed by immunohistochemistry for P-Cadherin and WNT5A. A survival analysis was also performed. Results: The expression levels of P-Cadherin and WNT5A in OSCC groups were statistically significant between metastatic and non-metastatic groups (p < 0.001). P-Cadherin and WNT5A expression in metastatic (lymph node metastasis) and non-metastatic cases showed a significant correlation coefficient of 0.753 at (p < 0.01). The present study also found that the aberrant expression (high) of P-Cadherin was associated with diminished survival of patients with metastatic OSCC. Conclusion: The present study demonstrated the aberrant expression of P-Cadherin and WNT5A could serve as important prognosticator in OSCC. Clinical relevance: P-Cadherin and WNT5A could be used as significant predictors of disease outcome. [ABSTRACT FROM AUTHOR]

Purpose: Persistent infection with high-risk human papillomavirus (HR-HPV) is thought to play a prominent role in the initiation and progression of almost all cases of cervical cancer. Previously, we and others found that microRNA 34a (miR-34a) may be regulated by HR-HPV E6 to contribute to the development of cervical cancer. Here, we aimed to identify the oncogenic potential and clinical significance of a known miR-34a target, WNT1, in cervical squamous cell carcinoma (SCC) development and to investigate the associated mechanisms underlying cervical SCC cell proliferation and invasion. Methods: WNT1 and miR-34a expression levels were assessed in primary cervical lesions using immunohistochemistry and qRT-PCR, respectively. The cellular effects and the expression of its associated genes were examined in cervical SCC-derived Siha and Caski cells after siRNA-WNT1 (downregulation) or miR-34a mimic (upregulation) treatment. A cervical SCC xenograft mouse model was used to investigate the in vivo effects of miR-34a overexpression. HPV-16 E6/E7 expression was inhibited by gene promoter siRNA targeting, after which the levels of miR-34a and WNT1 were examined. Results: WNT1 protein upregulation was found to be associated with a poor prognosis in cervical SCC patients. In vitro assays in Siha and Caski cells revealed that WNT1 downregulation decreased cell proliferation and invasion, inhibited WNT/β-catenin activation and affected the expression of E-cadherin and P-cadherin. MiR-34a upregulation resulted in decreased WNT1 expression. An inverse correlation between miR-34a and WNT1 expression was also observed in primary cervical SCC tissues. In addition, we found that MiR-34a could regulate an E-cadherin to P-cadherin switch (E-P cadherin switch) to inhibit cell proliferation and tumorigenesis in vitro and in vivo via inactivation of the WNT1/β-catenin pathway. Finally, we found that decreased HPV-16 E6/E7 expression resulted in miR-34a upregulation and WNT1 downregulation in Siha and Caski cells. Conclusions: From our results we conclude that WNT1, as a target of miR-34a, can promote cervical SCC cell proliferation and invasion by induction of an E-P cadherin switch via the WNT1/β-catenin pathway. Our results may provide new options for the treatment of patients with cervical SCC. [ABSTRACT FROM AUTHOR]

Purpose: P-cadherin (CDH3), located at 16q22.1 belonging to classical cadherin family, is a calcium-dependent glycoprotein associated with cell to cell adhesion, migration, and invasion in cancer. This meta-analysis was conducted to examine the prognostic utility of P-cadherin expression in breast cancer (BC). Methods: A comprehensive literature search was carried out using the available databases to obtain relevant research articles to test the relationship between P-cadherin and BC. Correlation of P-cadherin expression and disease-free survival (DFS) or overall survival (OS) was tested using hazard ratio (HR), relative risk (RR) at 95% confidence interval (CI) by univariate and/or multivariate analysis. A total of 11 studies from 7 countries were found to be relevant and were further subjected to statistical analysis to find an association between the P-cadherin expression with BC. Additionally, we have also performed a co-relation analysis of P-cadherin expression with GOBO and Cancertool in breast cancer using publicly available breast cancer datasets. Results: Our study shows that P-cadherin expression is significantly linked with poor prognosis in the various subtypes of BC. The HR for OS and DFS was 1.87 (95% CI = 1.48–2.36) and 1.64 (95% CI = 1.18–2.27) respectively. Conclusions: In this meta-analysis, we identified a positive correlation between the overexpression of P-cadherin and BC. Our study demonstrates that P-cadherin overexpression can be used as a prognostic indicator in BC. [ABSTRACT FROM AUTHOR]

Cadherins seem to play and important role in prostate cancer (PCa) progression. E-cadherin loss of expression has been associated with poor prognosis; P-cadherin's role is still elusive. Although pT3 PCa is often considered "high-risk cancer," it does not exhibit an uniformly poor prognosis. Herein, we assessed the prognostic value and survival impact of E-cadherin and P-cadherin immunoexpression in pT3 PCa. Radical prostatectomy (RP) specimens from 102 pT3 PCa patients treated between 1991 and 2014 in a single institution were designated for E-cadherin and P-cadherin immunoexpression analysis. A representative block from each specimen was selected for tissue micro-array (TMA) construction, using 3 cores per case. E-cadherin immunoexpression was assessed via a digital image analysis system. For P-cadherin, scoring criteria for HER2 in gastric cancer were used. Clinical records of all patients were reviewed for baseline clinical/pathologic characteristics and follow-up data. E-cadherin-low PCa patients displayed worse disease-specific survival (DSS), although not reaching statistical significance (HR 2.65, 95%CI 0.81-7.88). However, considering the pT3b group only, those with low E-cadherin immunoexpression displayed significantly worse overall-survival (OS) and DSS (HR 3.69, 95%CI 1.18-11.50; HR 5.90, 95%CI 1.40-24.81). No significant differences in survival were found for P-cadherin differential immunoexpression. Furthermore, an association between E-cadherin and P-cadherin immunoexpression (p = 0.019) was found, as among E-cadherin-low PCa, 96.6% were P-cadherin negative. We demonstrated that low E-cadherin immunoexpression discriminates among pT3b PCa patients those with poorer survival and which might benefit from specific therapy. The role of P-cadherin in PCa seems context-dependent deserving further investigation. [ABSTRACT FROM AUTHOR]

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition. [ABSTRACT FROM AUTHOR]

Adherens junctions (AJs) are one of the major intercellular junctions in various epithelia including the epidermis and the follicular epithelium. AJs connect the cell surface to the actin cytoskeleton and comprise classic transmembrane cadherins, such as P-cadherin, armadillo family proteins, and actin microfilaments. Loss-of-function mutations in CDH3, which encodes P-cadherin, result in two allelic autosomal recessive disorders: hypotrichosis with juvenile macular dystrophy (HJMD) and ectodermal dysplasia, ectrodactyly, and macular dystrophy (EEM) syndromes. Both syndromes feature sparse hair heralding progressive macular dystrophy. EEM syndrome is characterized in addition by ectodermal and limb defects. Recent studies have demonstrated that, together with its involvement in cell-cell adhesion, P-cadherin plays a crucial role in regulating cell signaling, malignant transformation, and other major intercellular processes. Here, we review the roles of P-cadherin in skin and hair biology, with emphasize on human hair growth, cycling and pigmentation. [ABSTRACT FROM AUTHOR]

Breast cancer is considered as one of the multifactorial diseases. The aim of the current study is to investigate the association between P-cadherin and molecular subtypes of breast cancer, especially the basal-like subtype. Two hundred and thirteen breast-invasive ductal carcinomas were involved in this study. The expressions of P-cadherin were detected via immunohistochemistry. The 213 cases were divided into luminal A, luminal B, HER2 overexpression subtype, and normal breast-like and basal-like subtypes according to the standard of molecular breast cancer subtypes. In addition, the expressions of CK5/6 and CK14 were detected to distinguish between the normal breast-like and the basal-like subtypes. P-cadherin expression was found in 91 cases of 213 breast-invasive ductal carcinomas, with a positive rate of 42.7 %. P-cadherin correlated negatively with estrogen receptor (ER) ( p = 0.001) and progesterone receptor ( p = 0.001), whereas it positively correlated with histologic grade ( p = 0.003), NPI ( p = 0.005), p53 ( p = 0.038), and Ki67 ( p = 0.022). P-cadherin expression showed a strong correlation with recurrence and distant metastasis ( p = 0.009), and invasion of the vascular and soft tissues ( p = 0.004). Moreover, P-cadherin expression existed in the basal-like and non-basal-like subtypes. During prognosis, P-cadherin expression was associated with decreased disease-free survival in patients ( p = 0.009) and overall survival (OS) ( p = 0.005). In addition, multivariate analysis showed that tumor grade ( p = 0.021), ER ( p = 0.015), clinical stage ( p = 0.001), and P-cadherin ( p = 0.033) were significant predictors of OS. The current data suggest that P-cadherin may be used to distinguish the basal-like subtype and to predict the outcome in view of the relationship with DFS and OS. Furthermore, P-cadherin expression may be useful in making treatment decisions. [ABSTRACT FROM AUTHOR]

Cell–cell adhesion is an elementary process in normal epithelial cellular architecture. Several studies have shown the role mediated by cadherins in this process, besides their role in the maintenance of cell polarity, differentiation and cell growth. However, during tumour progression, these molecules are frequently altered. In breast cancer, tumours that overexpress P-cadherin usually present a high histological grade, show decreased cell polarity and are associated with worse patient survival. However, little is known about how this protein dictates the very aggressive behaviour of these tumours. To achieve this goal, we set up two breast cancer cell models, where P-cadherin expression was differently modulated and analysed in terms of cell invasion, motility and migration. We show that P-cadherin overexpression, in breast cancer cells with wild-type E-cadherin, promotes cell invasion, motility and migration. Moreover, we found that the overexpression of P-cadherin induces the secretion of matrix metalloproteases, specifically MMP-1 and MMP-2, which then lead to P-cadherin ectodomain cleavage. Further, we showed that soluble P-cadherin fragment is able to induce in vitro invasion of breast cancer cells. Overall, our results contribute to elucidate the mechanism underlying the invasive behaviour of P-cadherin expressing breast tumours. [ABSTRACT FROM AUTHOR]

Background: Although systemic responses to carbon dioxide (CO(2)) pneumoperitoneum have been studied, there have been few reports of local responses within the peritoneum. We investigated the expression of mRNA for adhesion molecules involved in cell-cell interactions, including ICAM-1, VCAM-1, CD44, E-cadherin, P-cadherin, and N-cadherin, after the induction of a CO(2) pneumoperitoneum in mice.Methods: Mice were treated with CO(2) pneumoperitoneum (4-6 mmHg for 30 min) and then killed after 24 h, 48 h, and 72 h. The peritoneum of the abdominal wall was resected, and total RNA was extracted by the acid guanidinium thiocyanate-phenol-chloroform extraction procedure, cDNA were synthesized by reverse transcription. Expression of the mRNA for each gene was normalized to that of b-actin for semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR).Results: The expression of P-cadherin mRNA was significantly increased at 48 h (p = 0.007) and returned to the control level by 72 h after CO(2) pneumoperitoneum. The expression of CD44 increased gradually, reaching a peak at 48 h and returning to the control value by 72 h after CO(2) pneumoperitoneum. Expression of ICAM-1 mRNA was not changed significantly after the application of CO(2).Conclusion: The expression of P-cadherin mRNA in the peritoneum can be induced to repair injuries to mesothelial cells caused by CO(2) pneumoperitoneum. [ABSTRACT FROM AUTHOR]