CDH13 is an atypical member of the cadherin family and is closely related to the clinicopathological factors and prognosis of many types of cancer. However, the role of CDH13 in clear cell renal cell carcinoma (ccRCC) remains unknown. Therefore, we comprehensively analyzed the expression level, diagnostic efficacy, clinical significance, prognostic value, immune infiltration, methylation status, genetic alteration, and biological functions of CDH13 in ccRCC patients. The results showed that CDH13 was significantly upregulated in ccRCC and strongly correlated with better survival, lower cancer stages, and lower tumor grades of ccRCC patients. Additionally, the immune infiltration analysis indicated that CDH13 might play a crucial role in regulating the tumor microenvironment of ccRCC. The results of methylation analysis showed that the epigenetic status of CDH13 was altered, and the prognosis of ccRCC patients was related not only to DNA methylation but also to m6A modification of CDH13. Finally, the results based on clinical samples further elucidated the expression pattern of CDH13 in ccRCC. In conclusion, CDH13 might be a novel prognostic biomarker and therapeutic target for patients with ccRCC. And our study provides new insights into the potential molecular changes and strategies for the treatment of ccRCC.

DNA methylation is one of the epigenetic mechanisms to regulate gene expression and frequently occurs in human cancer cells. T-cadherin (CDH13) is a new member of the cadherin superfamily and possesses multiple functions. Our study included 26 normal controls (NCs), 65 chronic hepatitis B patients (CHB), 14 liver cirrhosis patients (LC) and 157 hepatocellular carcinoma patients (HCC). We mainly focused on the mRNA expression and methylation status of CDH13 in peripheral blood mononuclear cells (PBMCs), which were detected by semi-quantitative real-time polymerase chain reaction (RT-qPCR) and methylation-specific polymerase chain reaction (MSP) respectively. The CDH13 mRNA level was lower in HCC, especially in early-stage of HCC than in NCs and CHB groups (p < 0.05). Methylation frequency of the CDH13 promoter was significantly higher in HCC patients than in the NCs and CHB groups (67.52 % vs 0.00 %, p < 0.001, 67.52 % vs 52.31 %, p < 0.05, respectively). CDH13 mRNA level was significantly and relatively lower in methylated groups than in unmethylated groups among the whole participants. The methylation level of CDH13 promoter in HCC might be influenced or partly influenced by some critical factors such as TBil, ALB and AFP (p < 0.05). As an important factor in signaling pathway regulating by CDH13 to promote carcinogenesis, JNK level was significantly higher in HCC which had a higher methylation frequency than in NCs, CHB and LC (p < 0.05). Furthermore, the combination of the methylated CDH13 level and AFP level showed a better score: AUC = 0.796 (SE = 0.031, 95 %CI 0.735-0.857; p < 0.001) in male and AUC = 0.832 (SE = 0.057, 95 %CI 0.721-0.944; p < 0.001) in female compared to AFP alone for diagnosing HCC from NCs, CHB and LC. The methylation of CDH13 promoter was an independent predictor for assessing the prognosis of HCC patients (r=-1.378 p < 0.05). In conclusion, hypermethylation of CDH13 in PBMCs was associated with the underexpression of mRNA and the high risk of HCC. The methylation status of the CDH13 promoter in PBMCs was a potential noninvasive biomarker to predict the prognosis of HCC patients.

Cadherin 13 (CDH13) is an atypical cadherin that exerts tumor-suppressive effects on cancers derived from epithelial cells. Although the CDH13 promoter is frequently hypermethylated in pancreatic cancer (PC), the direct impact of CDH13 on PC is unknown. Accordingly, the expression of CDH13 in PC cell lines and paired PC tissues was examined by immunohistochemistry, quantitative real-time PCR and western blotting. Our findings showed that CDH13 was downregulated in PC tissues and cell lines. Moreover, cell proliferation, migration and invasion were detected by CCK-8 assay, transwell migration assay and transwell invasion assay, respectively. Xenograft tumor experiments were used to determine the biological function of CDH13 in vivo. As revealed by our data, CDH13 overexpression significantly inhibited the proliferation, migration and invasion of human PC cells in vitro. The inhibitory effect of CDH13 on PC was further confirmed in animal models. Mice subcutaneously or orthotopically transplanted with CDH13-overexpressing CFPAC-1 cells developed significantly smaller tumors with less liver metastases and mesenteric metastases than those of the control group. Next, transcriptomics and western blot analysis were used to identify the underlying mechanisms. Further molecular mechanism studies showed that CDH13 overexpression inhibited the activation of the Wnt/β-catenin signaling pathway and regulated the expression of epithelial-mesenchymal transition (EMT)-related markers. Our results indicated that CDH13 displayed an inhibitory effect on PC and suggested that CDH13 might be a potential biomarker and a new therapeutic target for PC.

Background: Promoter methylation of tumour suppressor genes (TSGs) CDKN2A, CDKN2B and CDH13 has been reported in ovarian cancer. However, the clinicopathological characteristics and prognostic role of CDKN2A, CDKN2B and CDH13 promoter methylation in ovarian carcinoma remained unclear. Methods: The pooled odds ratio (OR) or hazard ratios (HRs) with their 95% confidence intervals (95% CIs) were calculated in this meta-analysis. The Cancer Genome Atlas data were obtained to confirm the role of CDKN2A, CDKN2B and CDH13 methylation in ovarian cancer. Results: CDKN2A, CDKN2B and CDH13 promoter methylation was higher in ovarian cancer than in normal ovarian tissues. CDH13 promoter methylation was correlated with tumour histology (serous vs. non-serous type: OR = 0.33, p = 0.031). CDKN2A promoter methylation was not linked to overall survival (OS), but it was correlated with a poor prognosis in progression-free survival (HR = 1.55, p = 0.004). TCGA data showed no correlation between CDKN2A, CDKN2B and CDH13 methylation and OS as well as disease-free survival (DFS). Conclusions: CDKN2A, CDKN2B and CDH13 promoter methylation may correlate with the increased risk of ovarian cancer. CDKN2A promoter methylation may be an independent prognostic biomarker for predicting progression-free survival.

Reversing cisplatin resistance of lung cancer cell line A549/DDP through recovering cadherin 13 (CDH13) expression by demethylation was investigated in the current study. RT-PCR was used to measure CDH13 expression in lung cancer A549 and A549/DDP cells with or without 5-Aza-CdR intervention. Methylation-specific PCR was used to detect CDH13 methylation. MTT assay and flow cytometry were used to measure the effects of cisplatin on inhibiting cell proliferation, apoptosis, and the reversal of cisplatin resistance. The IC50 value of cisplatin for A549 and A549/DDP cells was 3.278±0.532 and 28.341±1.435 µmol/l, respectively (P<0.05). The cisplatin-resistance index of A549/DDP cells was up to 8.65. After 2.5, 10, or 40 µmol/l 5-Aza-CdR treatment, the apoptotic rates of A549/DDP cells were 9.4±0.86, 18.1±1.42 and 42±2.01%, respectively, which were significantly different to those of the control group (P<0.05). Methylation-specific PCR detected both methylation (M) and unmethylation (U) bands at CDH13 promoter region before 5-Aza-CdR intervention while it only detected an unmethylation band after the treatment with a higher concentration of 5-Aza-CdR, which indicates the transformation to unmethylation state. When 10 µmol/l 5-Aza-CdR was added, the IC50 of cisplatin to A549/DDP cells was 8.472±0.415 µmol/l, and cisplatin resistance was reversed by 3.35-fold. CDH13 methylation is related to the cisplatin resistance of A549/DDP cells. 5-Aza-CdR can inhibit CDH13 methylation and recover CDH13 expression. With the increase in 5-Aza-CdR concentration, the unmethylation state of CDH13 is enhanced, which can strengthen the function of cisplatin inhibiting proliferation and apoptosis in A549/DDP cells.

Left ventricular mass index (LVMI) provides a metric for cardiovascular disease risk. We aimed to assess the association of adiponectin-related genetic variants resulting from GWAS in East Asians (loci in/near CDH13, ADIPOQ, WDR11FGF, CMIP and PEPD) with LVMI, and to examine whether sleep duration modified these genetic associations in youth. The 559 subjects aged 15-28 years were recruited from the Beijing Child and Adolescent Metabolic Syndrome study. Among the six loci, CDH13 rs4783244 was significantly correlated with adiponectin levels (p = 8.07 × 10-7). The adiponectin-rising allele in rs4783244 locus was significantly associated with decreased LVMI (p = 6.99 × 10-4) after adjusting for classical cardiovascular risk factors, and further for adiponectin levels, while no significant association was found between the other loci and LVMI. Moreover, we observed a significant interaction effect between rs4783244 and sleep duration (p = .005) for LVMI; the genetic association was more evident in long sleep duration while lost in short sleep duration. Similar interaction was found in the subgroup analysis using longitudinal data (p = .025 for interaction). In this young Chinese population, CDH13 rs4783244 represents a key locus for cardiac structure, and confers stronger cardio-protection in longer sleep duration when contrasted with short sleep duration.

OBJECTIVE: To understand the relationships between CDH13 (T-cadherin) genetic polymorphisms, adiponectin levels and ischemic stroke, and possible interactions between CDH13 polymorphisms and other risk factors.
METHODS: We recruited 342 Chinese ischemic stroke sib pairs. We genotyped rs4783244 and rs7193788 on CDH13 using time-of-flight mass spectrometry genotyping technology and measured total and high-molecular weight (HMW) adiponectin levels. We investigated associations between SNPs and ischemic stroke, and interactions between SNPs and other risk factors using multi-level mixed-effects regression model.
RESULTS: In individuals without ischemic stroke, CDH13 rs4783244 was associated with total adiponectin levels (per T: Coef = -0.257, P = 0.001). CDH13 rs7193788 was associated with total adiponectin levels (per A: Coef = -0.221, P = 0.001) and HMW adiponectin levels (per A: Coef = -0.163, P = 0.003). rs7193788 was significantly associated with ischemic stroke (GA/AA vs. GG: OR = 1.55, 95% CI: 1.07 to 2.24, P = 0.020) after Bonferroni correction (α = 0.025). There was an interaction between rs7193788 and diabetes (P = 0.036). Compared to diabetes-free individuals with rs7193788 GG genotype, diabetes patients with rs7193788 GA/AA genotypes had higher risks for ischemic stroke (OR = 2.64, 95% CI: 1.58-4.40, P < 0.001).
CONCLUSIONS: CDH13 genetic polymorphisms are associated with adiponectin levels and ischemic stroke. An interaction is found between CDH13 SNP and diabetes for ischemic stroke.

Background: Aberrant methylation of CpG islands in tumor cells in promoter regions is a critical event in non-small cell lung carcinoma (NSCLC) tumorigenesis and can be a potential diagnostic biomarker for NSCLC patients. The present study systemically and quantitatively reviewed the diagnostic ability of CDH13 methylation in NSCLC as well as in its subsets. Eligible studies were identified through searching PubMed, Web of Science, Cochrane Library and Embase. The pooled odds of CDH13 promoter methylation in lung cancer tissues versus normal controls were calculated by meta-analysis method. Simultaneously, four independent DNA methylation datasets of NSCLC from TCGA and GEO database were downloaded and analyzed to validate the results from meta-analysis. Results: Thirteen studies, including 1850 samples were included in this meta-analysis. The pooled odds ratio of CDH13 promoter methylation in cancer tissues was 7.41 (95% CI: 5.34 to 10.29, P < 0.00001) compared with that in controls under fixed-effect model. In validation stage, 126 paired samples from TCGA were analyzed and 5 out of the 6 CpG sites in the CpG island of CDH13 were significantly hypermethylated in lung adenocarcinoma tissues but none of the 6 CpG sites was hypermethylated in squamous cell carcinoma tissues. Concordantly, the results from other three datasets, which were subsequently obtained from GEO database consisting of 568 tumors and 256 normal tissues, also consisted with those from TCGA dataset. Conclusion: The pooled data showed that the methylation status of the CDH13 promoter is strongly associated with lung adenocarcinoma. The CDH13 methylation status could be a promising diagnostic biomarker for diagnosis of lung adenocarcinoma.

In order to elucidate the role of epigenetic alterations in the development of cutaneous squamous cell carcinoma (SCC), we analyzed both gene-specific promoter hypermethylation and repetitive sequence hypomethylation in cutaneous SCC as well as normal skin tissue samples. We showed that methylation of DAPK1 and CDH13 was associated with cutaneous SCC. While methylation frequency of DAPK1 was increased from sun-protected normal skin, sun-exposed normal skin, perilesional to lesional tissues, methylation of CDH13 was almost exclusively detected in cutaneous SCC tissues. Further, methylation of DAPK1 and CDH13 was neither correlated with the presence of HPV nor with the presence of p53 mutations in lesional skin tissues. Finally, we detected trend of reduced methylation level of repetitive sequences from sun-protected, sun-exposed normal skin samples to perilesional, and lesional tissues from SCC patients. We conclude that both gene-specific hypermethylation and repetitive sequence hypomethylation are present in cutaneous SCC tissue samples; these epigenetic changes might represent an independent pathway in the development of cutaneous SCC.