PCDH10

Gene Summary

Gene:PCDH10; protocadherin 10
Aliases: PCDH19, OL-PCDH
Location:4q28.3
Summary:This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. This family member contains 6 extracellular cadherin domains, a transmembrane domain and a cytoplasmic tail differing from those of the classical cadherins. The encoded protein is a cadherin-related neuronal receptor thought to function in the establishment of specific cell-cell connections in the brain. This gene plays a role in inhibiting cancer cell motility and cell migration. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2015]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protocadherin-10
HPRD
Source:NCBIAccessed: 11 August, 2015

Ontology:

What does this gene/protein do?
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Cancer Overview

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Publications Per Year (1990-2015)
Graph generated 11 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 August, 2015 using data from PubMed, MeSH and CancerIndex

Latest Publications: PCDH10 (cancer-related)

Deng J, Liang H, Ying G, et al.
Clinical significance of the methylated cytosine-phosphate-guanine sites of protocadherin-10 promoter for evaluating the prognosis of gastric cancer.
J Am Coll Surg. 2014; 219(5):904-13 [PubMed] Related Publications
BACKGROUND: Protocadherin-10 (PCDH10) has been identified as a tumor suppressor gene in multiple carcinomas. In this study, we intended to elucidate the clinical applicability of the methylation of CpG sites of PCDH10 promoter for prognostic prediction in gastric cancer (GC).
STUDY DESIGN: Qualitative and quantitative detections of PCDH10 promoter methylation were performed with methylation-specific polymerase chain reaction (MSP) and bisulphite genomic sequencing, respectively. The methylated statuses of 27 cytosine-phosphate-guanine (CpG) sites in PCDH10 promoter were detected in a series of 458 GC tissues to supply precise information of prognostic prediction. Associations between molecular, clinicopathologic, and survival data were analyzed.
RESULTS: Protocadherin-10 promoter methylation was found in 91.92% in all patients. Gastric cancer patients with 5 or more methylated CpG sites of PCDH10 promoter was significantly associated with poorer survival (p = 0.038). Meanwhile, methylation of combined CpG (-115, -108, -13, and +3) sites was also identified to provide elaborate survival discrimination for GC patients (p = 0.044). On multivariate survival analysis, methylation of combined CpG (-115, -108, -13, and +3) sites (hazard ratio [HR] = 1.255; p = 0.049) was identified to be an independent prognostic indicator of GC, as were N stage and T stage. Additionally, the methylation of combined CpG (-115, -108, -13, and +3) sites had smaller Akaike information criterion (AIC) and Bayesian information criterion (BIC) values than the other 2 independent predictors of the survival. Ultimately, we demonstrated that the methylation of combined CpG (-115, -108, -13, and +3) sites was negatively associated with PCDH10 expression in GC tissues.
CONCLUSIONS: The methylated CpG sites of PCDH10 promoter had significant applicability for clinical evaluation of the prognosis of GC.

Wang L, Xie PG, Lin YL, et al.
Aberrant methylation of PCDH10 predicts worse biochemical recurrence-free survival in patients with prostate cancer after radical prostatectomy.
Med Sci Monit. 2014; 20:1363-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Prostate cancer is a common malignancy in men, and inevitably some patients experience biochemical recurrence after radical prostatectomy. To date, there are no reliable predictors for prostate cancer recurrence, and novel predictors are urgently needed. PCDH10 (protocadherin-10) is a novel tumor suppressor gene, which is down-regulated by promoter methylation in prostate cancer. The aim of this study was to evaluate the feasibility of using PCDH10 methylation to predict the biochemical recurrence (BCR) of prostate cancer after radical prostatectomy.
MATERIAL/METHODS: Fresh tissue samples were obtained from 151 patients with primary prostate cancer, and from 34 patients with benign prostatic hyperplasia (BPH) as control. The methylation status of PCDH10 in prostate cancer tissues and controls were examined using methylation-specific PCR (MSP), and then associated with clinicopathological features and BCR-free survival of patients with prostate cancer.
RESULTS: We found that PCDH10 methylation was detected in 79 (52.3%) patients with prostate cancer, but no methylation was found in controls (P<0.0001). Moreover, PCDH10 methylation was significantly associated with higher preoperative prostate-specific antigen (PSA) level (P <0.0001), higher Gleason Score (P<0.0001), advanced clinical stage (P=0.0002), lymph node metastasis (P=0.0389), angiolymphatic invasion (P=0.0303), and biochemical recurrence (P=0.0068). Moreover, PCDH10 methylation was associated with poor BCR-free survival (P<0.0001), and may be used as an independent predictor of BCR-free survival (P=0.0046).
CONCLUSIONS: Our results indicate that PCDH10 methylation in prostate cancer tissue is an independent prognostic biomarker of worse BCR-free survival of patients with prostate cancer after radical prostatectomy.

Zhao Y, Yang Y, Trovik J, et al.
A novel wnt regulatory axis in endometrioid endometrial cancer.
Cancer Res. 2014; 74(18):5103-17 [PubMed] Related Publications
The Protocadherin 10 (PCDH10) is inactivated often by promoter hypermethylation in various human tumors, but its possible functional role as a tumor suppressor gene is not established. In this study, we identify PCDH10 as a novel Wnt pathway regulatory element in endometrioid endometrial carcinoma (EEC). PCDH10 was downregulated in EEC tumor cells by aberrant methylation of its promoter. Restoring PCDH10 levels suppressed cell growth and triggered apoptosis in EEC cells and tumor xenografts. Gene expression profiling revealed as part of the transcriptomic changes induced by PCDH10 a reduction in levels of MALAT1, a long noncoding RNA, that mediated tumor suppression functions of PCDH10 in EEC cells. We found that MALAT1 transcription was regulated by Wnt/β-catenin signaling via TCF promoter binding and PCDH10 decreased MALAT1 by modulating this pathway. Clinically, MALAT1 expression was associated with multiple parameters in patients with EEC. Taken together, our findings establish a novel PCDH10-Wnt/β-catenin-MALAT1 regulatory axis that contributes to EEC development. Cancer Res; 74(18); 5103-17. ©2014 AACR.

Li Z, Yang Z, Peng X, et al.
Nuclear factor-κB is involved in the protocadherin-10-mediated pro-apoptotic effect in multiple myeloma.
Mol Med Rep. 2014; 10(2):832-8 [PubMed] Related Publications
The gene encoding protocadherin-10 (PCDH10), a member of the cadherin superfamily, has been recently identified as a tumor suppressor gene (TSG). PCDH10 plays important roles in the apoptosis of tumor cells in some cancer types. However, the exact role of PCDH10 in multiple myeloma (MM) is largely unknown. Increasing evidence has suggested that the activation of nuclear factor-κB (NF-κB) is crucial for apoptosis in myeloma cells. In this study, we investigated the pro-apoptotic effect of PCDH10 on myeloma cells and whether this effect may involve inhibition of the NF-κB pathway. We report here, for the first time to the best of our knowledge, that PCDH10 markedly induces apoptosis of myeloma cells, accompanied by an increase in activated caspase-3 and poly-ADP‑ribose polymerase (PARP) levels, and inhibited expression of anti‑apoptotic proteins. We also demonstrate that PCDH10 inhibits the activation of NF-κB, by inhibiting the expression of the inhibitor of nuclear factor-κB (IκB) kinase subunits (IKKs) and the phosphorylation of IκBα. Moreover, the constitutive NF-κB DNA-binding activity and the expression of the NF-κB‑regulated proteins cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and intercellular adhesion molecule 1 (ICAM-1) were inhibited by PCDH10 in MM cells. These results suggest that PCDH10 induces myeloma cell apoptosis, probably by inhibiting the NF-κB pathway.

Jao TM, Tsai MH, Lio HY, et al.
Protocadherin 10 suppresses tumorigenesis and metastasis in colorectal cancer and its genetic loss predicts adverse prognosis.
Int J Cancer. 2014; 135(11):2593-603 [PubMed] Related Publications
Protocadherin 10 (PCDH10), a novel tumor suppressor gene in human cancers, is located in a common deleted region at chromosome 4q28 in colorectal cancer (CRC). This study aimed to ascertain the genetic loss of PCDH10 and its clinical relevance in CRC and to explore the tumor suppressor function of PCDH10. The genetic deletion of PCDH10 was determined in 171 pairs of primary tumors and corresponding normal mucosae by loss of heterozygosity study. In total, 53 carcinomas were positive for allelic loss of PCDH10. The genetic aberration was significantly associated with tumor progression and distant metastasis (p = 0.021 and p = 0.018, respectively) and was an independent predictor of poor survival for CRC patients (p = 0.005). Expression of PCDH10 gene was silenced or markedly down-regulated in all of 12 CRC cell lines tested and in 41 of 53 colorectal carcinomas compared with their matched normal mucosae. Ectopic expression of PCDH10 suppressed cancer cell proliferation, anchorage-independent growth, migration and invasion in vitro. Subcutaneous injection of PCDH10-expressing CRC cells into SCID mice revealed the reduction of tumor growth compared with that observed in mock-inoculated mice. Furthermore, through intrasplenic implantation, the re-expression of PCDH10 in silenced cells restrained liver metastasis and improved survival in SCID mice. In conclusion, PCDH10 is a pivotal tumor suppressor in CRC, and the loss of its function promotes not only tumor progression but also liver metastasis. In addition, the genetic deletion of PCDH10 represents an adverse prognostic marker for the survival of patients with CRC.

Echizen K, Nakada M, Hayashi T, et al.
PCDH10 is required for the tumorigenicity of glioblastoma cells.
Biochem Biophys Res Commun. 2014; 444(1):13-8 [PubMed] Related Publications
Protocadherin10 (PCDH10)/OL-protocadherin is a cadherin-related transmembrane protein that has multiple roles in the brain, including facilitating specific cell-cell connections, cell migration and axon guidance. It has recently been reported that PCDH10 functions as a tumor suppressor and that its overexpression inhibits proliferation or invasion of multiple tumor cells. However, the function of PCDH10 in glioblastoma cells has not been elucidated. In contrast to previous reports on other tumors, we show here that suppression of the expression of PCDH10 by RNA interference (RNAi) induces the growth arrest and apoptosis of glioblastoma cells in vitro. Furthermore, we demonstrate that knockdown of PCDH10 inhibits the growth of glioblastoma cells xenografted into immunocompromised mice. These results suggest that PCDH10 is required for the proliferation and tumorigenicity of glioblastoma cells. We speculate that PCDH10 may be a promising target for the therapy of glioblastoma.

Heitzer E, Artl M, Filipits M, et al.
Differential survival trends of stage II colorectal cancer patients relate to promoter methylation status of PCDH10, SPARC, and UCHL1.
Mod Pathol. 2014; 27(6):906-15 [PubMed] Related Publications
Surgical excision of colorectal cancer at early clinical stages is highly effective, but 20-30% of patients relapse. Therefore, it is of clinical relevance to identify patients at high risk for recurrence, who would benefit from adjuvant chemotherapy. The objective of this study was to identify prognostic and/or predictive methylation markers in stage II colorectal cancer patients. Therefore, we selected six gene promoters (FZD9, PCDH10 (protocadherin 10), SFRP2, SPARC (secreted protein acidic and rich in cysteine), UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), and WIF1) for methylation analysis in formalin-fixed, paraffin-embedded primary tumor samples of colorectal cancer patients (n=143) who were enrolled in a prospective randomized phase III trial of the Austrian Breast and Colorectal cancer Study Group. Patients were randomized to adjuvant chemotherapy with 5-fluorouracil and leucovorin or surveillance only. Survival analyses revealed that combined evaluation of three promoters (PCDH10, SPARC, and UCHL1) showed differential effects with regard to disease-free survival and overall survival in the two treatment groups (significance level 0.007). In the chemotherapy arm, a statistically insignificant trend for patients without methylation toward longer survival was observed (P=0.069 for disease-free survival and P=0.139 for overall survival). Contrary, patients in the surveillance arm without methylation in their gene promoters had shorter disease-free survival and overall survival (P=0.031 for disease-free survival and P=0.003 for overall survival), indicating a prognostic effect of methylation in this group (test for interaction, P=0.006 for disease-free survival and P=0.018 for overall survival). These results indicate that promoter methylation status of PCDH10, SPARC, and UCHL1 may be used both as prognostic and predictive molecular marker for colorectal cancer patients and, therefore, may facilitate treatment decisions for stage II colorectal cancer.

Schneider BG, Piazuelo MB, Sicinschi LA, et al.
Virulence of infecting Helicobacter pylori strains and intensity of mononuclear cell infiltration are associated with levels of DNA hypermethylation in gastric mucosae.
Epigenetics. 2013; 8(11):1153-61 [PubMed] Free Access to Full Article Related Publications
DNA methylation changes are known to occur in gastric cancers and in premalignant lesions of the gastric mucosae. In order to examine variables associated with methylation levels, we quantitatively evaluated DNA methylation in tumors, non-tumor gastric mucosae, and in gastric biopsies at promoters of 5 genes with methylation alterations that discriminate gastric cancers from non-tumor epithelia (EN1, PCDH10, RSPO2, ZIC1, and ZNF610). Among Colombian subjects at high and low risk for gastric cancer, biopsies from subjects from the high-risk region had significantly higher levels of methylation at these 5 genes than samples from subjects in the low risk region (p ≤ 0.003). When results were stratified by Helicobacter pylori infection status, infection with a cagA positive, vacA s1m1 strain was significantly associated with highest methylation levels, compared with other strains (p = 0.024 to 0.001). More severe gastric inflammation and more advanced precancerous lesions were also associated with higher levels of DNA methylation (p ≤ 0.001). In a multivariate model, location of residence of the subject and the presence of cagA and vacA s1m1 in the H. pylori strain were independent variables associated with higher methylation in all 5 genes. High levels of mononuclear cell infiltration were significantly related to methylation in PCDH10, RSPO2, and ZIC1 genes. These results indicate that for these genes, levels of methylation in precancerous lesions are related to H. pylori virulence, geographic region and measures of chronic inflammation. These genes seem predisposed to sustain significant quantitative changes in DNA methylation at early stages of the gastric precancerous process.

Narayan G, Xie D, Freddy AJ, et al.
PCDH10 promoter hypermethylation is frequent in most histologic subtypes of mature lymphoid malignancies and occurs early in lymphomagenesis.
Genes Chromosomes Cancer. 2013; 52(11):1030-41 [PubMed] Related Publications
PCDH10 is epigenetically inactivated in multiple tumor types; however, studies in mature lymphoid malignancies are limited. Here, we have investigated the presence of promoter hypermethylation of the PCDH10 gene in a large cohort of well-characterized subsets of lymphomas. PCDH10 promoter hypermethylation was identified by methylation-specific PCR in 57 to 100% of both primary B- and T-cell lymphoma specimens and cell lines. These findings were further validated by Sequenom Mass-array analysis. Promoter hypermethylation was also identified in 28.6% cases of reactive follicular hyperplasia, more commonly occurring in states of immune deregulation and associated with rare presence of clonal karyotypic aberrations, suggesting that PCDH10 methylation occurs early in lymphomagenesis. PCDH10 expression was down regulated via promoter hypermethylation in T- and B-cell lymphoma cell lines. The transcriptional down-regulation resulting from PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases in cell lines. Both T- and B-cell lymphoma cell lines harboring methylation-mediated inactivation of PCDH10 were resistant to doxorubicin treatment, suggesting that hypermethylation of this gene might contribute to chemotherapy response.

Danese E, Minicozzi AM, Benati M, et al.
Epigenetic alteration: new insights moving from tissue to plasma - the example of PCDH10 promoter methylation in colorectal cancer.
Br J Cancer. 2013; 109(3):807-13 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumour-released DNA in blood represents a promising biomarker for cancer detection. Although epigenetic alterations such as aberrant promoter methylation represent an appealing perspective, the discordance existing between frequencies of alterations found in DNA extracted from tumour tissue and cell-free DNA (cfDNA) has challenged their practical clinical application. With the aim to explain this bias of agreement, we investigated whether protocadherin 10 (PCDH10) promoter methylation in tissue was associated with methylation pattern in matched cfDNA isolated from plasma of patients with colorectal cancer (CRC), and whether the strength of concordance may depend on levels of cfDNA, integrity index, as well as on different clinical-pathological features.
METHODS: A quantitative methylation-specific PCR was used to analyse a selected CpG site in the PCDH10 promoter of 67 tumour tissues, paired normal mucosae, and matched plasma samples. The cfDNA integrity index and cfDNA concentration were assessed using a real-time PCR assay.
RESULTS: The PCDH10 promoter methylation was detected in 63 out of 67 (94.0%) surgically resected colorectal tumours and in 42 out of 67 (62.7%) plasma samples. The median methylation rate in tumour tissues and plasma samples was 43.5% (6.3-97.8%) and 5.9% (0-80.9%), respectively. There was a significant correlation between PCDH10 methylation in cfDNA and tumour tissue in patients with early CRC (P<0.0001). The ratio between plasma and tissue methylation rate increases with increasing cfDNA integrity index in early-stage cancers (P=0.0299) and with absolute cfDNA concentration in advanced cancers (P=0.0234).
CONCLUSION: Our findings provide new insight into biological aspects modulating the concordance between tissues and plasma methylation profiles.

Qu Y, Dang S, Hou P
Gene methylation in gastric cancer.
Clin Chim Acta. 2013; 424:53-65 [PubMed] Related Publications
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.

Ma JG, He ZK, Ma JH, et al.
Downregulation of protocadherin-10 expression correlates with malignant behaviour and poor prognosis in human bladder cancer.
J Int Med Res. 2013; 41(1):38-47 [PubMed] Related Publications
OBJECTIVES: This study retrospectively evaluated the prognostic significance of downregulated protocadherin-10 (PCDH10) gene expression in bladder cancer.
METHODS: To evaluate the prognostic significance of downregulated PCDH10 protein levels, immunohistochemistry was used to assess the level of PCDH10 protein in surgically-resected formalin-fixed, paraffin wax-embedded transitional cell carcinoma specimens. Relationships between PCDH10 protein levels, clinicopathological characteristics and overall survival were also evaluated.
RESULTS: A total of 105 bladder transitional cell carcinoma specimens and 33 normal bladder epithelial samples were investigated using immunohistochemical staining. PCDH10 protein levels were downregulated in 63.8% (67/105) of bladder cancer specimens compared with control samples. Downregulated levels of PCDH10 were significantly associated with advanced stage, higher grade, larger tumour size, nonpapillary shape, tumour recurrence and decreased overall survival rates. Multivariate analysis indicated that downregulated PCDH10 levels were independently associated with decreased overall survival and had a relative risk of death of 4.571.
CONCLUSIONS: Downregulated PCDH10 levels correlated with malignant behaviour and poor overall survival in patients with bladder cancer. Downregulated PCDH10 levels might be useful as a prognostic biomarker for bladder cancer.

Tang X, Yin X, Xiang T, et al.
Protocadherin 10 is frequently downregulated by promoter methylation and functions as a tumor suppressor gene in non-small cell lung cancer.
Cancer Biomark. 2012-2013; 12(1):11-9 [PubMed] Related Publications
PURPOSE: Protocadherin 10 (PCDH10), a homophilic cell adhesion member of the protocadherin family, plays important roles in calcium-dependent cell-cell adhesion and signal transduction. PCDH10 expression is downregulated in a number of different malignances, predominantly through promoter methylation-driven silencing. This study was designed to investigate PCDH10 expression and promoter methylation status in non-small cell lung cancer (NSCLC), and biological effects of PCDH10 in lung cancer cells.
METHODS: The mRNA levels and promoter methylation status of PCDH10 were examined by RT-PCR and methylation-specific PCR (MSP) in lung cancer cell lines as well as primary lung tissue samples, and the clinical correlation of PCDH10 promoter methylation in NSCLC was further analyzed. The effects of PCDH10 re-expression in lung cancer cell lines was determined by cell proliferation, colony formation, and wound healing assays.
RESULTS: PCDH10 expression was downregulated or silenced in 4/8 lung cancer cell lines but could be restored by treatment with 5-aza-2'-deoxycytidine and trichostatin A. PCDH10 was also downregulated in NSCLC tissues compared to their corresponding adjacent tissues. Promoter methylation of PCDH10 was observed in 50% (20/40) of the NSCLC tissues but not in tumor-adjacent or normal tissues, and PCDH10 promoter methylation was statistically related to smoking. Ectopic expression of PCDH10 in silenced cells can reduce lung cancer cell proliferation and migration.
CONCLUSION: PCDH10 is frequently downregulated by promoter methylation and may serve as a tumor suppressor gene (TSG) in NSCLC.

Lin YL, Li ZG, He ZK, et al.
Clinical and prognostic significance of protocadherin-10 (PCDH10) promoter methylation in bladder cancer.
J Int Med Res. 2012; 40(6):2117-23 [PubMed] Related Publications
OBJECTIVE: To investigate the clinical and prognostic significance of protocadherin-10 (PCDH10) promoter methylation in serum-derived DNA from patients with bladder cancer.
METHODS: PCDH10 promoter methylation status was determined using methylation-specific polymerase chain reaction of DNA extracted from serum of patients with bladder cancer, and age- and sex-matched controls. Clinical and pathological details of bladder cancer were recorded.
RESULTS: PCDH10 promoter methylation was detected in 59/117 (50.4%) of patients with bladder cancer, and none of 37 (0%) controls. Methylation was significantly associated with advanced stage (T(2)-T(4)), high grade (G(3)), tumour recurrence and larger tumour size (> 3 cm). In addition, methylation was associated with significantly worse survival and was an independent predictor of overall survival.
CONCLUSION: Serum-based analysis of PCDH10 promoter methylation may represent a useful noninvasive biomarker of malignant behaviour and outcome in bladder cancer.

Zhong X, Zhu Y, Mao J, et al.
Frequent epigenetic silencing of PCDH10 by methylation in human colorectal cancer.
J Cancer Res Clin Oncol. 2013; 139(3):485-90 [PubMed] Related Publications
PURPOSE: Aberrant DNA methylation is common in cancer cells. Epigenetic alterations resulting in the loss of tumor suppression gene functions are frequently involved in tumor development and progression. Recently, methylation of PCDH10 was reported to be associated with multiple hematologic malignancies as well as some solid tumors. Whether the down-regulation of PCDH10 happens in CRC remains unknown.
METHODS: Methylation status of PCDH10 was evaluated by methylation-specific PCR analysis. The effects of PCDH10 re-expression were determined in growth, colony formation, cell cycle, and invasion assays.
RESULTS: In this study, we found that 100 % (8 of 8) of colorectal cancer cell lines were silenced for PCDH10, but not normal colorectal epithelial cells. Demethylation treatment confirmed that the reduced expression is associated closely with promoter methylation. Hyper-methylation of PCDH10 was also detected in 85 % of primary colorectal tumors, but not in adjacent normal colorectal tissues.
CONCLUSIONS: Our results suggest that PCDH10 is an important tumor suppression gene with key roles of suppressing cell proliferation, clonogenicity, and inhibiting cell invasion in the development of colorectal cancer. Thus, PCDH10 methylation may constitute a useful biomarker of colorectal cancer patients.

Lin YL, Li ZG, Guan TY
The clinical significance of PCDH10 promoter methylation in patients with bladder transitional cell carcinoma.
Urol Int. 2013; 90(2):219-24 [PubMed] Related Publications
OBJECTIVE: To investigate the clinical significance of PCDH10 (protocadherin 10) promoter methylation in patients with bladder transitional cell carcinoma (TCC).
MATERIALS AND METHODS: 107 samples of bladder TCC and 38 normal bladder epithelial tissues were investigated using methylation-specific PCR, and the relationships between PCDH10 methylation and clinicopathologic features as well as patients' outcome were analyzed.
RESULTS: PCDH10 methylation was detected in 63 (58.9%) bladder TCC samples, but no methylation of PCDH10 was found in controls. Moreover, PCDH10 methylation was significantly associated with larger tumor size (p = 0.0074), non-papillary shape (p = 0.0268), tumor relapse (p = 0.0029), high grade (p = 0.0397), advanced stage (p = 0.0004) and poor prognosis (p = 0.0009). In addition, multivariate analysis indicated that PCDH10 methylation is independently associated with poor outcome and may be used as a useful independent prognostic factor (p = 0.0255).
CONCLUSIONS: PCDH10 methylation is closely associated with malignancy of bladder TCC and may be used as an independent predictor for patients with bladder TCC.

Merwick A, O'Brien M, Delanty N
Complex single gene disorders and epilepsy.
Epilepsia. 2012; 53 Suppl 4:81-91 [PubMed] Related Publications
Epilepsy is a heterogeneous group of disorders, often associated with significant comorbidity, such as intellectual disability and skin disorder. The genetic underpinnings of many epilepsies are still being elucidated, and we expect further advances over the coming 5 years, as genetic technology improves and prices fall for whole exome and whole genome sequencing. At present, there are several well-characterized complex epilepsies associated with single gene disorders; we review some of these here. They include well-recognized syndromes such as tuberous sclerosis complex, epilepsy associated with Rett syndrome, some of the progressive myoclonic epilepsies, and novel disorders such as epilepsy associated with mutations in the PCDH 19 gene. These disorders are important in informing genetic testing to confirm a diagnosis and to permit better understanding of the variability in phenotype-genotype correlation.

Fang S, Huang SF, Cao J, et al.
Silencing of PCDH10 in hepatocellular carcinoma via de novo DNA methylation independent of HBV infection or HBX expression.
Clin Exp Med. 2013; 13(2):127-34 [PubMed] Related Publications
PCDH10 is a key tumor suppressive gene for nasopharyngeal, esophageal, and other carcinomas with frequent methylation. In this study, we investigated the potential epigenetic modification of the PCDH10 gene by hepatitis B virus × protein (HBx), a pivotal factor in the progression of HBV replication and potential carcinogenesis. PCDH10 expression was found to be down-regulated in 9/13 (69.2 %) of hepatocellular carcinoma (HCC) cell lines. Decreased PCDH10 expression was correlated with the methylation status of the PCDH10 promoter. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (Aza) was sufficient to restore PCDH10 mRNA expression by suppressing PCDH10 promoter methylation in HepG2 cells. Treatment with Trichostatin A alone had no significant effect on PCDH10 expression but enhanced the effect of Aza. PCDH10 methylation was further detected in 76 % (38 of 50) of HCC tissues compared with 40 % (20 of 50) of paired adjacent tissues, with no methylation detected in normal human liver tissues. There were significant correlations between methylation status of PCDH10 and tumor size, serum AFP levels, metastasis or TNM staging (P < 0.05). Moreover, PCDH10 promoter methylation status was not associated with HBV infection in our panel of 50 primary HCC tumors, and transfection with HBX could not alter the status of PCDH10 promoter methylation. Collectively, these observations suggested that the expression of PCDH10 was silenced in HCC via de novo DNA methylation independent of HBV infection or HBX expression, and PCDH10 might form a potentially useful therapeutic target for HCC.

Li Y, Yang ZS, Song JJ, et al.
Protocadherin-10 is involved in angiogenesis and methylation correlated with multiple myeloma.
Int J Mol Med. 2012; 29(4):704-10 [PubMed] Free Access to Full Article Related Publications
Protocadherin-10 (PCDH10) which is located at 4q28.3, is a member of the cadherin superfamily of cell adhesion molecules. PCDH10 is broadly expressed in normal adult, but nearly undetectable in multiple myeloma (ΜΜ) tissues and cell lines. Its promoter methylation was detected in virtually all the silenced or downregulated cell lines. The silencing of PCDH10 could be reversed by pharmacological demethylation, indicating a methylation-mediated mechanism. In the current study, we investigated 44 patients (23 females, 21 males), 77.27% (34/44) of whom presented high methylation of PCDH10. We found no associations between promoter hypermethylation and gender or age at the time of initial diagnosis. We also examined the role of PCDH10 as a mediator of MM cell proliferation, cell cycle progression, and its involvement in angiogenesis. Our results demonstrate that the PCDH10 gene is a target for epigenetic silencing in MM and provide a link between the dysregulation of angiogenesis and DNA methylation.

Li Z, Chim JC, Yang M, et al.
Role of PCDH10 and its hypermethylation in human gastric cancer.
Biochim Biophys Acta. 2012; 1823(2):298-305 [PubMed] Related Publications
Epigenetic changes of genomic DNA are involved in the development and progression of many cancers. Aberrant methylation of CpG islands in the promoter regions of certain tumor-suppressor genes (TSG) is frequently observed in cancer cells. Protocadherin 10 (PCDH10), a member of the cadherin superfamily, is a recently identified putative TSG. PCDH10 is frequently silenced in many solid tumors. However, the role of PCDH10 in gastric cancer is largely unknown. In this study, we examined the expression and methylation status of PCDH10 in gastric cancer cells and tissues by real time PCR and methylation-specific PCR (MSP), and then investigated the biological function of PCDH10. We found that the expression of PCDH10 was markedly reduced in gastric cancer cells and tissues. The reduced expression correlated with hypermethylation of this gene in its promoter region, as demonstrated by MSP and bisulfite genomic sequencing (BGS) analysis. In addition, pharmacological demethylation using 5-Aza restored the expression of PCDH10 in gastric cancer cells. Over-expression of PCDH10 in gastric cancer cells suppressed cell proliferation and migration, but did not cause marked apoptosis. Over-expression of PCDH10 also suppressed growth of xenograft tumors in nude mice. Thus, PCDH10 functions as a TSG in gastric cancer, and might be a useful target for cancer therapy.

Narayan G, Freddy AJ, Xie D, et al.
Promoter methylation-mediated inactivation of PCDH10 in acute lymphoblastic leukemia contributes to chemotherapy resistance.
Genes Chromosomes Cancer. 2011; 50(12):1043-53 [PubMed] Related Publications
PCDH10 has been implicated as a tumor suppressor, since epigenetic alterations of this gene have been noted in multiple tumor types. However, to date, studies regarding its role in acute and chronic leukemias are lacking. Here, we have investigated the presence of promoter hypermethylation of two CpG islands of the PCDH10 gene by methylation-specific PCR in 215 cases of various subsets of myeloid- and lymphoid-lineage leukemias. We found that PCDH10 promoter hypermethylation was frequent in both B-cell (81.9%) and T-cell (80%) acute lymphoblastic leukemia (ALL), while it was present in low frequency in most subtypes of myeloid leukemias (25.9%) and rare in chronic myeloid leukemia (2.2%). PCDH10 expression was downregulated via promoter hypermethylation in primary ALL samples (N = 4) and leukemia cell lines (N = 11). The transcriptional repression caused by PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases. ALL cell lines harboring methylation-mediated inactivation of PCDH10 were less sensitive to commonly used leukemia-specific drugs suggesting that PCDH10 methylation might serve as a biomarker of chemotherapy response. Our results demonstrate that PCDH10 is a target of epigenetic silencing in ALL, a phenomenon that may impact lymphoid-lineage leukemogenesis, serve as an indicator of drug resistance and may also have potential implications for targeted epigenetic therapy.

Bertrand KC, Mack SC, Northcott PA, et al.
PCDH10 is a candidate tumour suppressor gene in medulloblastoma.
Childs Nerv Syst. 2011; 27(8):1243-9 [PubMed] Related Publications
PURPOSE: The aim of this study was to investigate the genetic and epigenetic mechanisms contributing to PCDH10 down-regulation in medulloblastoma. We examined the role of PCDH10 as a mediator of medulloblastoma cell proliferation, cell cycle progression, and cell migration.
METHODS: We identified a focal homozygous deletion of PCDH10 in medulloblastoma by surveying a cohort of 212 tumours by Affymetrix SNP array analysis. PCDH10 expression was assessed by quantitative reverse transcriptase PCR in a series of 26 tumours. The promoter methylation status of PCDH10 was determined using methylation specific PCR and Sequenom MassCLEAVE analysis. Functional studies examining the role of PCDH10 in medulloblastoma development were performed by re-expression of PCDH10 in the DAOY medulloblastoma cell line, and then, cell proliferation, cell cycle distribution, and cell migration assays were performed.
RESULTS: We report a very focal homozygous deletion on chromosome 4q28.3 harbouring the PCDH10 gene. We demonstrate that PCDH10 transcription is down-regulated in 19/26 (73%) of medulloblastomas suggesting that other mechanisms also could be involved in gene repression. We found that DNA hypermethylation contributed to the deregulation of PCDH10 in 11/44 (25%) of medulloblastoma cell lines and primary tumours. Using a stable cell line (DAOY) re-expressing PCDH10, we observed that cell migration was impaired upon restoration of PCDH10 expression.
CONCLUSIONS: Our findings suggest that genetic and epigenetic deregulation of PCDH10 occurs in a significant portion of medulloblastoma patients. Failure to express PCDH10 may result in loss of inhibition of cell migration, thereby contributing to medulloblastoma progression.

Zhao SL, Zhu ST, Hao X, et al.
Effects of DNA methyltransferase 1 inhibition on esophageal squamous cell carcinoma.
Dis Esophagus. 2011; 24(8):601-10 [PubMed] Related Publications
To explore the role of DNA methyltransferase 1 (DNMT1) in esophageal squamous cell carcinoma (ESCC) and the potential of DNMT1-targeted small interfering RNA as ESCC therapy, we examined expression changes of DNMT1 in ESCC and investigated the effect of DNMT1 knockdown by RNA interference in a human ESCC cell line, KYSE30. DNMT1 messenger RNA was over-expressed in seven out of 12 ESCC samples, and the percentage of cells expressing DNMT1 was significantly higher in ESCC tissues compared with paired non-cancerous tissues. DNMT1 protein levels correlated with lymph node metastasis, but exhibited no correlation with sex, age, tumor site, or tumor differentiation. Knockdown of DNMT1 in KYSE30 cells using RNA interference resulted in a reduction of promoter methylation and re-expression of methyl-guanine methyl-transferase and retinoic acid receptors beta, inhibition of cell proliferation/viability and induction of cell apoptosis. These results indicate that DNMT1 over-expression is involved in ESCC and correlated with lymph node metastasis. Knockdown of DNMT1 led to promoter demethylation and re-expression of several tumor suppressor genes thereby inhibiting cell proliferation/viability and inducing cell apoptosis.

Li Z, Li W, Xie J, et al.
Epigenetic inactivation of PCDH10 in human prostate cancer cell lines.
Cell Biol Int. 2011; 35(7):671-6 [PubMed] Related Publications
PCDH10 (protocadherin-10), a novel tumour suppressor gene, is down-regulated in several human cancers due to hypermethylation of promoter CGIs (CpG islands). Here, we investigated the expression of PCDH10 in different normal adult tissues and in a panel of prostate cancer cell lines. PCDH10 was widely expressed in normal tissues with higher levels in the prostate. The expression of PCDH10 was markedly reduced or silenced in prostate cancer cell lines compared with normal adult prostate tissue. Decreased PCDH10 expression was correlated with the methylation status of the PCDH10 promoter. Furthermore, the DNA demethylating agent 5'-azacytidin restored PCDH10 expression by suppressing PCDH10 promoter methylation in prostate cancer cell lines. Treatment with Trichostatin A alone had no significant effect on the expression of PCDH10 but enhanced the effect of 5'-azacytidin. In conclusion, we found that the decreased PCDH10 expression in prostate cancer cells was associated with the aberrant methylation of PCDH10 promoter CGI. Our results may contribute to the understanding of the role of PCDH10 inactivation in the progression of prostate cancers.

Macones GA, Odibo A, Cahill A, Stamilio D
Discussion: 'Testing for biomarkers after ASC-US Pap smears' by Lin et al.
Am J Obstet Gynecol. 2011; 204(1):e12-3 [PubMed] Related Publications
In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Lin CJ, Lai H-C, Wang KH, et al. Testing for methylated PCDH10 or WT1 is superior to the HPV test in detecting severe neoplasms (CIN3 or greater) in the triage of ASC-US smear results. Am J Obstet Gynecol 2011;204:21.e1-7.

Kim SY, Yasuda S, Tanaka H, et al.
Non-clustered protocadherin.
Cell Adh Migr. 2011 Mar-Apr; 5(2):97-105 [PubMed] Free Access to Full Article Related Publications
The cadherin family is classified into classical cadherins, desmosomal cadherins and protocadherins (PCDHs). Genomic structures distinguish between PCDHs and other cadherins, and between clustered and non-clustered PCDHs. The phylogenetic analysis with full sequences of non-clustered PCDHs enabled them to be further classified into three subgroups: δ1 (PCDH1, PCDH7, PCDH9, PCDH11 and PCDH20), δ2 (PCDH8, PCDH10, PCDH12, PCDH17, PCDH18 and PCDH19) and ε (PCDH15, PCDH16, PCDH21 and MUCDHL). ε-PCDH members except PCDH21 have either higher or lower numbers of cadherin repeats than those of other PCDHs. Non-clustered PCDHs are expressed predominantly in the nervous system and have spatiotemporally diverse expression patterns. Especially, the region-specific expressions of non-clustered PCDHs have been observed in cortical area of early postnatal stage and in caudate putaman and/or hippocampal formation of mature brains, suggesting that non-clustered PCDHs play roles in the circuit formation and maintenance. The non-clustered PCDHs appear to have homophilic/heterophilc cell-cell adhesion properties, and each member has diverse cell signaling partnership distinct from those of other members (PCDH7/TAF1; PCDH8/TAO2β; PCDH10/Nap1; PCDH11/β-catenin; PCDH18/mDab1). Furthermore, each PCDH has several isoforms with differential cytoplasmic sequences, suggesting that one PCDH isoform could activate intracellular signaling differential from other isoforms. These facts suggest that non-clustered PCDHs play roles as a mediator of a regulator of other molecules as well as cell-cell adhesion. Furthermore, some non-clustered PCDHs have been considered to be involved in neuronal diseases such as autism-spectrum disorders, schizophrenia, and female-limited epilepsy and cognitive impairment, suggesting that they play multiple, tightly regulated roles in normal brain function. In addition, some non-clustered PCDHs have been suggested as candidate tumor suppressor genes in several tissues. Although molecular adhesive and regulatory properties of some PCDHs began to be unveiled, the endeavor to understand the molecular mechanism of non-clustered PCDH is still in its infancy and requires future study.

Lin CJ, Lai HC, Wang KH, et al.
Testing for methylated PCDH10 or WT1 is superior to the HPV test in detecting severe neoplasms (CIN3 or greater) in the triage of ASC-US smear results.
Am J Obstet Gynecol. 2011; 204(1):21.e1-7 [PubMed] Related Publications
OBJECTIVE: Management of equivocal Papanicolaou smear result remains to be challenging even with the aid of human papillomavirus test. Recently, 3 novel methylation-silenced genes, PAX1, WT1, and PCDH10, have been found to be specifically associated with cervical cancer. We compared the performances of methylation test of these genes with human papillomavirus tests in triage of equivocal Papanicolaou smear result.
STUDY DESIGN: Two hundred twenty-two women with Papanicolaou smear results of atypical cells of undetermined significance nested to a multicenter, nation-wide cohort (the T1899 cohort) were studied. Status of cervical neoplasm was diagnosed with colposcopic biopsy. Status of gene methylation was determined by methylation-specific polymerase chain reaction. High-risk human papillomavirus DNA was detected by polymerase chain reaction-reverse line blot hybridization and Hybrid Capture 2.
RESULTS: Cervical intraepithelial neoplasm 1, cervical intraepithelial neoplasm 2, cervical intraepithelial neoplasm 3, carcinoma in situ, carcinoma, and normal cervix were diagnosed in 58, 17, 14, 10, 1, and 120 women, respectively. Methylation of PCDH10, WT1, and PAX1 was highly associated with the severity of cervical neoplasm (P < 10⁻⁹, < 10⁻⁷, and < 10⁻⁵, respectively). In comparison with a negative test result, the odds ratio (95% confidence intervals) for cervical intraepithelial neoplasm 3 or more severe neoplasms for women tested positive for methylation of these 3 genes were 26.4 (9.0-77.3), 18.1 (6.9-47.2), and 10.3 (4.1-25.9), respectively; whereas those positive for human papillomavirus polymerase chain reaction and Hybrid Capture 2 were 10.5 (3.5-31.9) and 5.6 (2.3-21.4). In triage for atypical cells of undetermined significance, each methylation test had less colposcopy referral and false-positive rates, but higher false-negative rate than the human papillomavirus tests. With a combination test of PCDH10 or WT1 methylation, a comparable false-negative rate (P = .62) but much less false-positive rate (P = .002) and colposcopy referral rate (P < 10⁻⁶) were achieved.
CONCLUSION: In triage of atypical cells of undetermined significance Papanicolaou smear results, methylation test of WT1 and PCDH10 is superior to human papillomavirus test in this multicenter cohort. Comparing to current human papillomavirus triage, the new test has only one third of false positivity and half of colposcopy referral, with no compromise of the sensitivity in diagnosis of cervical intraepithelial neoplasm 3 or more severe neoplasms.

Yu B, Yang H, Zhang C, et al.
High-resolution melting analysis of PCDH10 methylation levels in gastric, colorectal and pancreatic cancers.
Neoplasma. 2010; 57(3):247-52 [PubMed] Related Publications
Protocadherins are celladhesion molecules with 6 or 7 cadherin motifs in their extracellular domain and various cyotoplasmic domains. PCDH10 was characterized a novel tumor suppressive gene in and was epigenetically silenced in multiple haematologic malignancies as well as some solid tumors such as gastric cancer, nasopharyngeal carcinoma and esophageal carcinoma. High-resolution melting (HRM) analysis has been used as a novel tool for analysis of promoter methylation. In our study, we used HRM analysis to detect the methylation levels of PCDH10 gene in 100 gastric cancers, 100 colorectal cancers, 70 pancreatic cancers and equal number of adjacent normal tissues. The frequency of PCDH10 methylation in all three types of cancers was significantly higher than that in normal tissues. Consistent with previous reports, expression levels of PCDH10 were inversely correlated with methylation levels. But we didn't find significant association between PCDH10 methylation status and TNM staging in all three types of cancers. In summary, application of HRM analysis to large amount of clinical samples proves to be a fast and high-throughput way to investigate the epigenetic status of PCDH10. And this is the first study to evaluate the prevalence of PCDH10 methylation based on large amount of tumor samples, showing that epigenetic regulation of PCDH10 was associated with carcinogenesis.

Cheung HH, Lee TL, Davis AJ, et al.
Genome-wide DNA methylation profiling reveals novel epigenetically regulated genes and non-coding RNAs in human testicular cancer.
Br J Cancer. 2010; 102(2):419-27 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Testicular germ cell tumour (TGCT) is the most common malignant tumour in young males. Although aberrant DNA methylation is implicated in the pathophysiology of many cancers, only a limited number of genes are known to be epigenetically changed in TGCT. This report documents the genome-wide analysis of differential methylation in an in vitro model culture system. Interesting genes were validated in TGCT patient samples.
METHODS: In this study, we used methylated DNA immunoprecipitation (MeDIP) and whole-genome tiling arrays to identify differentially methylated regions (DMRs).
RESULTS: We identified 35 208 DMRs. However, only a small number of DMRs mapped to promoters. A genome-wide analysis of gene expression revealed a group of differentially expressed genes that were regulated by DNA methylation. We identified several candidate genes, including APOLD1, PCDH10 and RGAG1, which were dysregulated in TGCT patient samples. Surprisingly, APOLD1 had previously been mapped to the TGCT susceptibility locus at 12p13.1, suggesting that it may be important in TGCT pathogenesis. We also observed aberrant methylation in the loci of some non-coding RNAs (ncRNAs). One of the ncRNAs, hsa-mir-199a, was downregulated in TGCT patient samples, and also in our in vitro model culture system.
CONCLUSION: This report is the first application of MeDIP-chip for identifying epigenetically regulated genes and ncRNAs in TGCT. We also demonstrated the function of intergenic and intronic DMRs in the regulation of ncRNAs.

Wang KH, Liu HW, Lin SR, et al.
Field methylation silencing of the protocadherin 10 gene in cervical carcinogenesis as a potential specific diagnostic test from cervical scrapings.
Cancer Sci. 2009; 100(11):2175-80 [PubMed] Related Publications
PCDH10 is a member of the protocadherin cell adhesion molecule family, which are frequently downregulated in cancers. This study aimed to characterize the methylation silencing of the PCDH10 gene in the full spectrum of cervical carcinogenesis and to clarify if a field effect of methylation might be a target for a diagnostic test from cervical scrapings. Methylation silencing of PCDH10 was found in four of five cervical cancers and one of two cervical precancerous cell lines, which could be reversed by demethylation treatment. The same methylation was detected in 85.7% (24/28) of invasive cancer tissues, 36.4% (4/11) of high-grade squamous intraepithelial lesions, 20% (1/5) of low-grade squamous intraepithelial lesions, and none (0/17) of the normal cervical tissues from non-cancer subjects. In addition, methylation was also frequently found in histologically 'normal' cervical tissues adjacent to cancer lesions (7/13, 53.8%) and, less frequently, in vaginal and endometrial tissues (1/8, 12.5%). Further investigation of cervical scrapings revealed cancer-specific methylation of PCDH10 with a methylation rate of 71% (22/31) in invasive cancer, 27.9% (12/43) in carcinoma in situ, and none in high-grade squamous intraepithelial lesions excluding carcinoma in situ (n = 12), low-grade squamous intraepithelial lesions (n = 27), and normal controls (n = 66) (P < 10(-16)). Compared to the high-risk human papilloma virus test, PCDH10 methylation testing of cervical scrapings was more specific (92 vs 60%) but less sensitive (71 vs 96%) in detecting invasive cervical cancer. This study demonstrated field methylation of the PCDH10 gene specifically in the invasion stage of cervical carcinogenesis, which might be used to develop a highly specific diagnostic test for cervical scrapings.

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