Cadherin 13 Research Articles

Virulence factors released from Porphyromonas gingivalis induce electrophysiological dysfunction in human pluripotent stem cell-derived cardiomyocytes

Background/purposePeriodontal disease development correlates with the occurrence of systemic diseases. The present study investigated the association between periodontal disease and the development of cardiac arrhythmia. Materials and methodsHuman embryonic stem cell-derived cardiomyocytes (hESC-CMs) were treated with Porphyromonas gingivalis (Pg). Cardiotoxicity and electrophysiological properties of hESC-CMs were measured using the cell counting kit-8 assay and a multi-electrode array, respectively. Reverse-transcription-quantitative polymerase chain reaction (RT-qPCR) revealed the mRNA expression of S100 calcium binding protein A1 (S100A1), calsequestrin 2 (CASQ2), troponin I3 (TNNI3), myosin light chain 2 (MYL2), integrin subunit beta 1 (ITGB1), and cadherin 2 (CDH2) in hESC-CMs. ResultsTreatment with Pg broth significantly decreased the beat period, field potential duration, spike amplitude, and conduction velocity without affecting the viability of hESC-CMs. In addition, the mRNA expression of CASQ2, TNNI3, and MYL2, which are all associated with calcium handling, were downregulated by Pg broth treatment. ConclusionThese findings indicate that Pg may induce cardiac arrhythmia mediated by virulence factors.

A panel of epigenetically dysregulated Wnt signaling pathway genes for non-invasive diagnosis of pediatric acute lymphoblastic leukemia.

Genetic and epigenetic dysregulation of Wnt signaling pathway is widely linked up with abnormal proliferation and/or epithelial-to-mesenchymal transition, in different cancer cell types. In the present research, we have tested whether promoter DNA methylation of a set of Wnt/non-Wnt genes such as [cadherin-2 (CDH2)], "present in circulation", could serve as "bone-marrow biopsy surrogate" and help in diagnosing the status, sub-type or treatment outcome in pediatric acute lymphoblastic leukemia (ALL) patients. Promoter DNA methylation was quantified in the bisulfite modified blood from the pediatric ALL patients (n= 86) in comparison with age-matched cancer-free subjects (n= 28), using real-time methylation specific PCR followed by rigorous statistical validations. The observed methylation index, sensitivity and specificity of selected molecular markers (viz., SALL1, WNT5α, LRP1b, CDH2) in patients' liquid-biopsies was clinically significant showing high positive correlation in the pre-B ALL cases (p-value < 0.001). A substantial drop in promoter methylation signal of the follow-up/post-treatment patients was also noted (p-value < 0.001), which suggested an impending role of minimally invasive liquid-biopsy approach in the diagnosis and/or therapeutic monitoring of pediatric leukemia. Whilst the reported metadata provides useful insight into the plausible involvement of epigenetic glitches in leukemogensis, our findings strengthen the remarkable functional consequences of dysregulated Wnt signaling genes in the hematological malignancies besides offering a novel panel of epigenetic marks.

SPAG5 Is Involved in Human Gliomagenesis Through the Regulation of Cell Proliferation and Apoptosis.

BackgroundGlioma is the most frequent malignant primary brain tumor in adults.ObjectiveTo explore the role of sperm-associated antigen 5 (SPAG5) in glioma.MethodsThe association between SPAG5 expression and clinical features was investigated based on The Cancer Genome Atlas (TCGA) datasets. The function of SPAG5 in glioma was analyzed using U87 and U251 cells. Knockdown glioma cells were constructed by shRNA interference. qRT-PCR and Western blotting were used to measure the expression of SPAG5 and Cadherin 2 (CDH2). Cell proliferation and apoptosis were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, caspase 3/7 assay, and high-content screening (HCS) proliferation analysis and colony formation assay. Transwell assays and wound-healing assays were used to investigate cell migration and invasion.ResultsThe increased expression of SPAG5 was correlated with poor outcomes in glioma patients. Knocking down SPAG5 could inhibit the proliferation and colony formation and promoted the apoptosis of glioma cells. Knocking down SPAG5 could also inhibit cell migration and invasion and the expression of CDH2. Overexpression of CDH2 with SPAG5 depletion could restore the proliferation and inhibit the apoptosis of glioma cells, which also promoted cell migration and invasion.ConclusionsSPAG5 is a promising prognostic factor and potential therapeutic target for clinical intervention in glioma.

MiR-145 suppresses the motility of prostate cancer cells by targeting cadherin-2.

Metastasis is the main cause of poor prognosis in the advanced prostate cancer in clinic. Accumulating evidences have proposed that cell motility greatly contributes to the multiple steps of the metastatic process. MicroRNA-145 (miR-145) has been found to be downregulated in prostate cancer and serve as a putative tumor suppressor via decrease of cell growth and augmentation of cell death; however, the effects and the underlying mechanisms of miR-145 in prostate cancer cell motility have not been completely clarified. In the current study, we first demonstrated that miR-145 exerted inhibitory effects on the aggressive phenotype of the prostate cancer cells. Based on the bioinformatics analysis of the putative target genes of miR-145, we further experimentally identified a novel mechanism of miR-145 suppressing the aggressive phenotype of prostate cancer cells via directly targeting cadherin-2 (CDH2) protein translation. Re-expression of CDH2 could rescue miR-145-triggered cell migration and invasion defects. Our results suggested that miR-145 suppressed the motility of prostate cancer cells via post-transcriptional downregulation of CDH2 expression, and miR-145-CDH2 pair might serve as a potential target for intervention of prostate cancer metastasis.

Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks

Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human-induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance.

Cadherin 2-Related Arrhythmogenic Cardiomyopathy

Background - Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibro-fatty replacement of the right and/or left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants, in the non-desmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM. Methods - A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2-positive probands, and clinical evaluation was assessed. Results - Genetic screening of CDH2 led to the identification of 7 rare variants: five, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and/or sudden cardiac death occurred in 5/9 (56%). Conclusions - In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.

Interactive association between dietary fat and sex on CDH13 cg02263260 methylation

BackgroundDNA methylation of Cadherin 13 (CDH13), a tumor suppressor gene is associated with gene repression and carcinogenesis. We determined the relation of dietary fat and sex with CDH13 cg02263260 methylation in Taiwanese adults.MethodsData of 870 eligible participants (430 men and 440 women) between 30 and 70 years were obtained from the Taiwan Biobank (TWB) database. The association of dietary fat and sex with CDH13 cg02263260 methylation was determined using multiple linear regression.ResultsThe association between sex and cg02263260 methylation was significant: beta-coefficient (β) = 0.00532; 95% confidence interval (CI) = 0.00195–0.00868. Moreover, the interaction between sex and dietary fat on cg02263260 methylation was significant (P-value = 0.0145). After stratification by sex, the association of dietary fat with cg02263260 methylation was significant only in women. Specifically, high dietary fat was positively associated with cg02263260 methylation in women (β = 0.00597; 95% CI = 0.00061–0.01133) and the test for trend was significant (P-value = 0.0283).ConclusionHigh fat intake was significantly associated with higher cg02263260 methylation in women and the test for trend was significant. These findings suggest that the association of fat intake and CDH13 cg02263260 might vary by sex and CDH13 cg02263260 methylation levels in women might increase as fat intake increases.

Transcriptional Profiling Reveals the Regulatory Role of DNER in Promoting Pancreatic Neuroendocrine Neoplasms.

Wnt/β-catenin and NOTCH signaling contribute to the pathogenesis and growth of (PanNENs). The wnt and Notch signaling pathways form an integrated signaling device termed “wntch” and regulate stochastic cell fate decisions, suggesting the essentiality of Wnt/Notch interactions in disease progression. However, the function of Wnt/Notch interactions in PanNENs is unclear. We analyzed RNA sequencing (RNA-seq) data to identify differentially expressed lncRNAs, mRNAs and pathways according to enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with PanNENs. RNA-seq analysis revealed that the levels of the lncRNA XLOC_221242 and the mRNA encoding Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER) were significantly increased in tumor tissues compared with normal tissues (n = 3). Protein-protein interaction (PPI) prediction combined with transcriptional profiling data analysis revealed that DNER expression levels were positively correlated with those of DNA-binding factor (RBPJ), S phase kinase-associated protein 1 (Skp1), CTNNB1 and Cadherin-2 (CDH2), which promote PanNEN tumorigenesis and progression. These results were consistent with those of immunohistochemical analysis of DNER, RBPJ, SKP1, CTNNB1, and CDH2 expression (n = 15). These findings provide compelling clinical and molecular evidence supporting the conclusion that DNER and the related RBPJ, SKP1, CTNNB1, and CDH2 signaling contribute to PanNEN tumorigenesis and progression by activating wnt/Notch interactions.

Comprehensive bioinformatics analysis of the TP53 signaling pathway in Wilms' tumor.

BackgroundDifferential expression of tumor protein 53 (TP53, or p53) has been observed in multiple cancers. However, the expression levels and prognostic role of TP53 signaling pathway genes in Wilms’ tumor (WT) have yet to be fully explored.MethodsThe expression levels of TP53 signaling pathway genes including TP53, mouse double minute 2 (MDM2), mouse double minute 4 (MDM4), cyclin-dependent kinase 2A (CDKN2A), cyclin-dependent kinase 2B (CDKN2B), and tumor suppressor p53-binding protein 1 (TP53BP1) in WT were analyzed using the Oncomine database. Aberration types, co-mutations, mutation locations, signaling pathways, and the prognostic role of TP53 in WT were investigated using cBioPortal. MicroRNA (miRNA) and transcription factor (TF) targets were identified with miRTarBase, miWalk, and ChIP-X Enrichment Analysis 3 (CheA3), respectively. A protein-protein network was constructed using GeneMANIA. The expression of TP53 signaling genes were confirmed in WT samples and normal kidney tissues using the Human Protein Atlas (HPA). Cancer Therapeutics Response Portal (CTRP) was used to analyze the small molecules potentially targeting TP53.ResultsTP53 was significantly expressed in the Cutcliffe Renal (P=0.010), but not in the Yusenko Renal (P=0.094). Meanwhile, MDM2 was significantly overexpressed in the Yusenko Renal (P=0.058), but not in the Cutcliffe Renal (P=0.058). The expression levels of MDM4 no significant difference between the tumor and normal tissue samples. The most common TP53 alteration was missense and the proportion of TP53 pathway-related mutations was 2.3%. Co-expressed genes included ZNF609 (zinc finger protein 609), WRAP53 (WD40-encoding RNA antisense to p53), CNOT2 (CC chemokine receptor 4-negative regulator of transcription 2), and CDH13 (cadherin 13). TP53 alterations indicated poor prognosis of WT (P=1.051e-4). The regulators of the TP53 pathway included miR-485-5p and TFs NR2F2 and KDM5B. The functions of TP53 signaling pathway were signal transduction in response to DNA damage and regulate the cell cycle. The small molecules targeting TP53 included PRIMA-1, RITA, SJ-172550, and SCH-529074.ConclusionsTP53 was found to be differentially expressed in WT tissues. TP53 mutations indicated poor outcomes of WT. Therefore, pifithrin-mu, PRIMA-1, RITA, SJ-172550, and SCH-529074 could be used in combination with traditional chemotherapy to treat WT.

Paris polyphylla ethanol extract induces G2/M arrest and suppresses migration and invasion in bladder cancer.

BackgroundParis polyphylla is a traditional Chinese medicinal herb with multiple antitumor activities, but the role of P. polyphylla in bladder cancer (BC) is under investigation. This study aims to examine the antitumor activities of P. polyphylla ethanol extract (PPE) on BC cells and elucidate the underlying mechanisms.MethodsViable cells were counted using the trypan blue exclusion assay. The cell cycle was analyzed using flow cytometry, and scratch wound-healing and transwell assays were used to evaluate cell migration and invasion abilities, respectively. The protein expression levels were determined by western blotting. A xenograft model was used to assess the in vivo inhibitory effect of PPE on BC tumor growth.ResultsOur results showed that PPE inhibited the growth of BC cells in vivo and in vitro. Mechanistically, PPE regulated the levels of cell cycle-associated proteins, with PPE-induced G2/M phase arrest occurring through cyclin-dependent kinase inhibitor 1 (CDKN1A) accumulation and cyclin B1 (CCNB1)/cyclin-dependent kinase 1 (CDK1) inhibition. BC tumor growth was also inhibited by PPE treatment. Moreover, the migration and invasion abilities of J82 cells were suppressed through modulating epithelial-mesenchymal transition (EMT) regulatory factors with upregulation of cadherin-1 (CDH1) and downregulation of cadherin-2 (CDH2), snail family transcriptional repressor 2 (SNAI2), and twist family bHLH transcription factor 1 (TWIST1).ConclusionsPPE inhibited cell growth, induced G2/M arrest, and suppressed the migration and invasion of J82 cells. BC tumor growth in vivo was also inhibited by PPE. Our results lay the foundation for further studies on the antitumor mechanisms of PPE.

Determination of genetic variation within the &amp;lt;i&amp;gt;DYRK2&amp;lt;/i&amp;gt; gene and its associations with milk traits in cattle

To speed up the progress of marker-assisted selection (MAS) in cattle breeding, the dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2), cadherin 2 (CDH2), and kinesin family member 1A (KIF1A) genes were chosen based on our pervious genome-wide association study (GWAS) analysis results. DYRK2 is a kinase that may participate in cell growth and/or development; it shows phosphorylation activity toward serine, threonine, and tyrosine fragments of proteins, and it is different from other protein kinases. The CDH2 gene encodes a classic cadherin, which is a member of the cadherin superfamily. The protein encoded by KIF1A is a member of the kinesin family and plays a role in the transportation of membrane organelles along axon microtubules. We detected insertion/deletion (InDel) variation in these three candidate genes in 438 individual cattle (Xinjiang Brown cattle and Wagyu Luxi crossbreed cattle). Only DYRK2-P3-11 bp was polymorphic and genotyped. The polymorphism information content of DYRK2-P3-11 bp was 0.336. Correlation analyses showed that InDel polymorphism was significantly associated with six different milk traits. These findings may aid future analyses of InDel genotypes in cattle breeds, and speed up the progress of MAS in cattle breeding.

Plasma proteomic profiling of young and old mice reveals cadherin-13 prevents age-related bone loss.

The blood exhibits a dynamic flux of proteins that are secreted by the tissues and cells of the body. To identify novel aging-related circulating proteins, we compared the plasma proteomic profiles of young and old mice using tandem mass spectrometry. The expression of 134 proteins differed between young and old mice. We selected seven proteins that were expressed at higher levels in young mice, and confirmed their plasma expression in immunoassays. The plasma levels of anthrax toxin receptor 2 (ANTXR2), cadherin-13 (CDH-13), scavenger receptor cysteine-rich type 1 protein M130 (CD163), cartilage oligomeric matrix protein (COMP), Dickkopf-related protein 3 (DKK3), periostin, and secretogranin-1 were all confirmed to decrease with age. We then investigated whether any of the secreted proteins influenced bone metabolism and found that CDH-13 inhibited osteoclast differentiation. CDH 13 treatment suppressed the receptor activator of NF-κB ligand (RANKL) signaling pathway in bone marrow-derived macrophages, and intraperitoneal administration of CDH-13 delayed age-related bone loss in the femurs of aged mice. These findings suggest that low plasma CDH-13 expression in aged mice promotes aging-associated osteopenia by facilitating excessive osteoclast formation. Thus, CDH-13 could have therapeutic potential as a protein drug for the prevention of osteopenia.

Discovering Therapeutic Protein Targets for Bladder Cancer Using Proteomic Data Analysis.

Bladder cancer accounts for almost 54% of urinary system cancer and is the second most frequent cause of death in genitourinary malignancies after prostate cancer. About 70% of bladder tumors are non-muscle-invasive, and the rest are muscle-invasive. Recurrence of the tumor is the common feature of bladder cancer. Chemotherapy is a conventional treatment for MIBC, but it cannot improve the survival rate of these patients sufficiently. Therefore, researchers must develop new therapies. Antibody-based therapy is one of the most important strategies for the treatment of solid tumors. Selecting a suitable target is the most critical step for this strategy. The aim of this study is to detect therapeutic cell surface antigen targets in bladder cancer using data obtained by proteomic studies. Isobaric tag for relative and absolute quantitation (iTRAQ) analysis had identified 131 overexpressed proteins in baldder cancer tissue and reverse-phase proteomic array (RPPA) analysis had been done for 343 tumor tissues and 208 antibodies. All identified proteins from two studies (131+208 proteins) were collected and duplicates were removed (331 unique proteins). Gene ontology study was performed using gene ontology (GO) and protein analysis through evolutionary relationships (PANTHER) databases. The Human Protein Atlas database was used to search the protein class and subcellular location of membrane proteins obtained from the PANTHER analysis. Membrane proteins that could be suitable therapeutic targets for bladder cancer were selected. These included: Epidermal growth factor receptor (EGFR), Her2, Kinase insert domain receptor (KDR), Heat shock protein 60 (HSP60), HSP90, Transferrin receptor (TFRC), Activin A Receptor Like Type 1 (ACVRL1), and cadherin 2 (CDH2). Monoclonal antibodies against these proteins or their inhibitors were used for the treatment of different cancers in preclinical and clinical trials. These monoclonal antibodies and inhibitor molecules and also their combination can be used for the treatment of bladder cancer.

Adhesion Molecules as Potential Novel Biomarkers for Opioid Dependence.

Cell-cell adhesion is essential in maintaining the structure and function of an organ. Several adhesion molecules have recently been identified as associated with heroin dependence in both genetic and peripheral plasma studies. We reviewed literature concerning studies on adhesion molecules in opioid addictions in rodents and human, including human genetic associations in different ethnic groups, and treatment responses to methadone maintenance treatment in heroin-dependent patients. Some important and novel findings were summarized and discussed. Adhesion molecules in the peripheral plasma, e.g., cadherin-2 (CDH2), may be biomarkers for both methadone treatment outcome and nectin 4 may be an indicator for continued opioid use. Neural cell adhesion molecule (NCAM) in the central nervous system may regulate opioid withdrawal and analgesic responses. Future studies to uncover the mechanisms underlying the involvement of adhesion molecules in the pathological process of addictions will be an important research direction in the field.

Serotonin (5-HT) neuron-specific inactivation of Cadherin-13 impacts 5-HT system formation and cognitive function

Genome-wide screening approaches identified the cell adhesion molecule Cadherin-13 (CDH13) as a risk factor for neurodevelopmental disorders, nevertheless the contribution of CDH13 to the disease mechanism remains obscure. CDH13 is involved in neurite outgrowth and axon guidance during early brain development and we previously provided evidence that constitutive CDH13 deficiency influences the formation of the raphe serotonin (5-HT) system by modifying neuron-radial glia interaction.Here, we dissect the specific impact of CDH13 on 5-HT system development and function using a 5-HT neuron-specific Cdh13 knockout mouse model (conditional Cdh13 knockout, Cdh13 cKO).Our results show that exclusive inactivation of CDH13 in 5-HT neurons selectively increases 5-HT neuron density in the embryonic dorsal raphe, with persistence into adulthood, and serotonergic innervation of the developing prefrontal cortex. At the behavioral level, adult Cdh13 cKO mice display delayed acquisition of several learning tasks and a subtle impulsive-like phenotype, with decreased latency in a sociability paradigm alongside with deficits in visuospatial memory. Anxiety-related traits were not observed in Cdh13 cKO mice.Our findings further support the critical role of CDH13 in the development of dorsal raphe 5-HT circuitries, a mechanism that may underlie specific clinical features observed in neurodevelopmental disorders.

Cadherin 13 Inhibits Pancreatic Cancer Progression and Epithelial-mesenchymal Transition by Wnt/β-Catenin Signaling.

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.

Down-Regulation of Circular RNA_000926 Attenuates Renal Cell Carcinoma Progression through miRNA-411–Dependent CDH2 Inhibition

Many studies have recognized that circular RNAs (circRNAs) can be promising targets for renal cell carcinoma (RCC) by acting as competing endogenous RNAs for miRNAs. This study intends to uncover the implication of a novel circRNA, circ_000926 in RCC, and how it affects tumorigenesis. Microarray-based circRNA/gene expression profiling of RCC was used to identify differentially expressed circRNAs/genes in RCC and normal tissues. miRNAs targeting the screened circRNAs/genes were predicted online, followed by analyzing circ_000926 expression in RCC. The crosstalk among circ_000926, miRNA-411 (miR-411), and CDH2 was then validated. The expression of circ_000926, miR-411, and cadherin 2 (CDH2) was up-regulated or down-regulated in RCC cells to unearth their effects on the biological behaviors of RCC cells. circ_000926 was highly expressed in RCC tissues and cell lines, whereas CDH2 was verified to be a target of miR-411. As a competing endogenous RNA, circ_000926 could directly bind to miR-411 to up-regulate CDH2. Down-regulation of circ_000926 resulted in inhibited growth, migration, and invasion abilities of RCC cells, as well as suppressed epithelial-mesenchymal transition and tumor growth. However, the inhibition of miR-411 or elevation of CDH2 reversed the antitumor effects induced by silencing circ_000926. Down-regulation of circ_000926 exerts an inhibitory effect on RCC progression through miR-411-dependent CDH2 inhibition, highlighting a potential target for RCC treatment.

MYB promotes the growth and metastasis of salivary adenoid cystic carcinoma.

The incidence of recurrent t(6;9) translocation of the MYB proto-oncogene to NFIB (the gene that encodes nuclear factor 1 B-type) in adenoid cystic carcinoma (ACC) tumour tissues is high. However, MYB [the gene that encodes transcriptional activator Myb (MYB)] overexpression is more common, indicating that MYB serves a key role in ACC. The current study aimed to investigate the role of MYB in salivary (S)ACC growth and metastasis. A total of 50 fresh-frozen SACC tissues and 41 fresh-frozen normal submandibular gland (SMG) tissues were collected to measure MYB mRNA expression, and to analyse the associations between MYB and epithelial-mesenchymal transition (EMT) markers. Compared with normal SMG tissue, SACC tissues demonstrated significantly increased MYB expression, with a high expression rate of 90%. Interestingly, MYB tended to be negatively correlated with CDH1 [the gene that encodes cadherin-1 (E-cadherin)] and positively correlated with VIM (the gene that encodes vimentin), suggesting that MYB is associated with SACC metastasis. To explore the role of MYB in SACC, the authors stably overexpressed and knocked down MYB in SACC cells. The authors of the current study demonstrated that MYB overexpression promoted SACC cell proliferation, migration and invasion, whereas its knockdown inhibited these activities. Additionally, when MYB was overexpressed, CDH1 expression was downregulated, and CDH2 (the gene that encodes cadherin-2), VIM and ACTA2 (the gene that encodes actin, aortic smooth muscle) expression was upregulated. Then, the effect of MYB on lung tumour metastasis was investigated in vivo in non-obese diabetic/severe combined immunodeficiency mice. MYB overexpressing and control cells were injected into the mice through the tail vein. The results revealed that MYB promoted SACC lung metastasis. Collectively, these results demonstrated that MYB is aberrantly overexpressed in SACC tissues, and promotes SACC cell proliferation and metastasis, indicating that MYB may be a novel therapeutic target for SACC.

Analysis of the association between CDH2 gene polymorphism and osteoarthritis risk.

to define the cadherin 2 (CDH2) gene polymorphism in Chinese osteoarthritis and control populations and to explore the correlation between CDH2 gene polymorphism and the risk of osteoarthritis. a total of 476 patients with osteoarthritis were collected and 380 control subjects were included in the study. Clinical data such as gender, age and functional score were collected. The blood and tissue samples were collected and genotyped by PCR. Data analysis was performed using SPSS 19.0, Hapioview 4.2 and SNPstats softwares. the association of rs11083271 and osteoarthritis was initially validated in this study population (P = 0.016, OR = 1.43 (1.07- 1.93)]. The risk of OA was significantly higher in heterozygous T/C than in homozygous T/T and C/C in rs11083271. By adjusting the age, according to gender stratification analysis, the heterozygous T/C genotype in rs11083271 significantly increased the risk of OA incidence in males [p = 0.011, 3.40 (1.55-7.43)]. The remaining rs sites were not significantly associated with OA. Notably, the association of rs11564299 with OA, regardless of genotyping, gene frequency and RNA expression levels in the study population, was not confirmed. in this study, we have analyzed the association between CDH2 gene polymorphism and OA in Chinese population. We found that rs11083271 heterozygous T/C genotype significantly increases the risk of OA and the severity of the disease. By contrast, the rs11564299 locus and OA have no significant correlation in the Chinese population. The role of rs11083271 in the regulation of CDH2 expression levels and the mechanisms by which it impacts OA remain to be further studied.

CDH13 promoter methylation regulates cisplatin resistance of non-small cell lung cancer cells.

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.