Cadherin 13 Research Articles

Serum proteome signatures associated with liver steatosis in adolescents with obesity.

Childhood obesity, a pressing global health issue, significantly increases the risk of metabolic complications, including metabolic dysfunction associated with steatotic liver disease (MASLD). Accurate non-invasive tests for early detection and screening of steatosis are crucial. In this study, we explored the serum proteome, identifying proteins as potential biomarkers for inclusion in non-invasive steatosis diagnosis tests. Fifty-nine obese adolescents underwent ultrasonography to assess steatosis. Serum samples were collected and analyzed by targeted proteomics with the Proximity Extension Assay technology. Clinical and biochemical parameters were evaluated, and correlations among them, the individuated markers, and steatosis were performed. Receiver operating characteristic (ROC) curves were used to determine the steatosis diagnostic performance of the identified candidates, the fatty liver index (FLI), and their combination in a logistic regression model. Significant differences were observed between subjects with and without steatosis in various clinical and biochemical parameters. Gender-related differences in the serum proteome were also noted. Five circulating proteins, including Cathepsin O (CTSO), Cadherin 2 (CDH2), and Prolyl endopeptidase (FAP), were identified as biomarkers for steatosis. CDH2, CTSO, Leukocyte Immunoglobulin Like Receptor A5 (LILRA5), BMI, waist circumference, HOMA-IR, and FLI, among others, significantly correlated with the steatosis degree. CDH2, FAP, and LDL combined in a logit model achieved a diagnostic performance with an AUC of 0.91 (95% CI 0.75-0.97, 100% sensitivity, 84% specificity). CDH2 and FAP combined with other clinical parameters, represent useful tools for accurate diagnosis of fatty liver, emphasizing the importance of integrating novel markers into diagnostic algorithms for MASLD.

A Comprehensive Analysis of Non-Desmosomal Rare Genetic Variants in Arrhythmogenic Cardiomyopathy: Integrating in Padua Cohort Literature-Derived Data.

Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disease at risk of sudden death. Genetic testing impacts greatly in ACM diagnosis, but gene-disease associations have yet to be determined for the increasing number of genes included in clinical panels. Genetic variants evaluation was undertaken for the most relevant non-desmosomal disease genes. We retrospectively studied 320 unrelated Italian ACM patients, including 243 cases with predominant right-ventricular (ARVC) and 77 cases with predominant left-ventricular (ALVC) involvement, who did not carry pathogenic/likely pathogenic (P/LP) variants in desmosome-coding genes. The aim was to assess rare genetic variants in transmembrane protein 43 (TMEM43), desmin (DES), phospholamban (PLN), filamin c (FLNC), cadherin 2 (CDH2), and tight junction protein 1 (TJP1), based on current adjudication guidelines and reappraisal on reported literature data. Thirty-five rare genetic variants, including 23 (64%) P/LP, were identified in 39 patients (16/243 ARVC; 23/77 ALVC): 22 FLNC, 9 DES, 2 TMEM43, and 2 CDH2. No P/LP variants were found in PLN and TJP1 genes. Gene-based burden analysis, including P/LP variants reported in literature, showed significant enrichment for TMEM43 (3.79-fold), DES (10.31-fold), PLN (117.8-fold) and FLNC (107-fold). A non-desmosomal rare genetic variant is found in a minority of ARVC patients but in about one third of ALVC patients; as such, clinical decision-making should be driven by genes with robust evidence. More than two thirds of non-desmosomal P/LP variants occur in FLNC.

A pyrazolopyridine as a novel AhR signaling activator with anti-breast cancer properties in vitro and in vivo

Breast cancer is one of the main causes of malignancy-related deaths globally and has a significant impact on women's quality of life. Despite significant therapeutic advances, there is a medical need for targeted therapies in breast cancer. Aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor mediates responses to environment stimuli, is emerging as a unique pleiotropic target. Herein, a combined molecular simulation and in vitro investigations identified 3-(3-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine (3FPP) as a novel AhR ligand in T47D and MDA-MB-231 breast cancer cells. Its agonistic effects induced formation of the AhR-AhR nuclear translocator (Arnt) heterodimer and prompted its binding to the penta-nucleotide sequence, called xenobiotic-responsive element (XRE) motif. Moreover, 3FPP augmented the promoter-driven luciferase activities and expression of AhR-regulated genes encoding cytochrome P450 1A1 (CYP1A1) and microRNA (miR)-212/132 cluster. It reduced cell viability, migration, and invasion of both cell lines through AhR signaling. These anticancer properties were concomitant with reduced levels of B-cell lymphoma 2 (BCL-2), SRY-related HMG-box4 (SOX4), snail family zinc finger 2 (SNAI2), and cadherin 2 (CDH2). In vivo, 3FPP suppressed tumor growth and activated AhR signaling in an orthotopic mouse model. In conclusion, our results introduce the fused pyrazolopyridine 3FPP as a novel AhR agonist with AhR-specific anti-breast cancer potential in vitro and in vivo.

The gene expression of CALD1, CDH2, and POSTN in fibroblast are related to idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung dysfunction due to excessive collagen production and tissue scarring. Despite recent advancements, the molecular mechanisms remain unclear. RNA sequencing identified 475 differentially expressed genes (DEGs) in the TGF-β1-induced primary lung fibrosis model. Gene expression chips GSE101286 and GSE110147 from NCBI gene expression omnibus (GEO) database were analyzed using GEO2R, revealing 94 DEGs in IPF lung tissue samples. The gene ontology (GO) and pathway enrichment, Protein-protein interaction (PPI) network construction, and Maximal Clique Centrality (MCC) scoring were performed. Experimental validation included RT-qPCR, Immunohistochemistry (IHC), and Western Blot, with siRNA used for gene knockdown. A co-expression network was constructed by GeneMANIA. GO enrichment highlighted significant enrichment of DEGs in TGF-β cellular response, connective tissue development, extracellular matrix components, and signaling pathways such as the AGE-RAGE signaling pathway and ECM-receptor interaction. PPI network analysis identified hub genes, including FN1, COL1A1, POSTN, KIF11, and ECT2. CALD1 (Caldesmon 1), CDH2 (Cadherin 2), and POSTN (Periostin) were identified as dysregulated hub genes in both the RNA sequencing and GEO datasets. Validation experiments confirmed the upregulation of CALD1, CDH2, and POSTN in TGF-β1-treated fibroblasts and IPF lung tissue samples. IHC experiments probed tissue-level expression patterns of these three molecules. Knockdown of CALD1, CDH2, and POSTN attenuated the expression of fibrotic markers (collagen I and α-SMA) in response to TGF-β1 stimulation in primary fibroblasts. Co-expression analysis revealed interactions between hub genes and predicted genes involved in actin cytoskeleton regulation and cell-cell junction organization. CALD1, CDH2, and POSTN, identified as potential contributors to pulmonary fibrosis, present promising therapeutic targets for IPF patients.

Transcriptomic analysis of glucosidase II beta subunit (GluIIß) knockout A549 cells reveals its roles in regulation of cell adhesion molecules (CAMs) and anti-tumor immunity

Glucosidase II beta subunit (GluIIß), encoded from PRKCSH, is a subunit of the glucosidase II enzyme responsible for quality control of N-linked glycoprotein folding and suppression of GluIIß led to inhibitory effect of the receptor tyrosine kinase (RTKs) activities known to be critical for survival and development of cancer. In this study, we investigated the effect of GluIIß knockout on the global gene expression of cancer cells and its impact on functions of immune cells. GluIIß knockout lung adenocarcinoma A549 cell line was generated using CRISPR/Cas9-based genome editing system and subjected to transcriptomic analysis. Among 23,502 expressed transcripts, 1068 genes were significantly up-regulated and 807 genes greatly down-regulated. The KEGG enrichment analysis showed significant down-regulation of genes related extracellular matrix (ECM), ECM-receptor interaction, cytokine-cytokine receptor interaction and cell adhesion molecules (CAMs) in GluIIß knockout cells. Of 9 CAMs encoded DEG identified by KEGG enrichment analysis, real time RT-PCR confirmed 8 genes to be significantly down-regulated in all 3 different GluIIß knockout clones, which includes cadherin 4 (CDH4), cadherin 2 (CDH2), versican (VCAN), integrin subunit alpha 4 (ITGA4), endothelial cell-selective adhesion molecule (ESAM), CD274 (program death ligand-1 (PD-L1)), Cell Adhesion Molecule 1 (CADM1), and Nectin Cell Adhesion Molecule 3 (NECTIN3). Whereas PTPRF (Protein Tyrosine Phosphatase Receptor Type F) was significantly decreased only in 1 out of 3 knockout clones. Microscopic analysis revealed distinctively different cell morphology of GluIIβ knockout cells with lesser cytoplasmic and cell surface area compared to parental A549 cells and non-targeted transfected cells.Further investigations revealed that Jurkat E6.1 T cells or human peripheral blood mononuclear cells (PBMCs) co-cultured with GluIIß knockout A549 exhibited significantly increased viability and tumor cell killing activity compared to those co-cultured with non-target transfected cells. Analysis of cytokine released from Jurkat E6.1 T cells co-cultured with GluIIß knockout A549 cells showed significant increased level of angiogenin and significant decreased level of ENA-78. In conclusion, knockout of GluIIß from cancer cells induced altered gene expression profile that improved anti-tumor activities of co-cultured T lymphocytes and PBMCs thus suppression of GluIIß may represent a novel approach of boosting anti-tumor immunity.

Molecular Mechanism of SOX18 in Lipopolysaccharide-Induced Injury of Human Umbilical Vein Endothelial Cells.

Endothelial dysfunction is associated with the progression of sepsis. This study sought to probe the molecular route of sex-determining region on the Y chromosome-box transcription factor 18 (SOX18) in sepsis-associated endothelial injury. Human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) to establish the sepsis cell model. Cell viability, lactate dehydrogenase (LDH) release, oxidative stress (reactive oxygen species/malondialdehyde/superoxide dismutase), and inflammation (interleukin-1β/tumor necrosis factor-α/interleukin-6) were evaluated by cell counting kit-8 assay and relevant assay kits. The expression levels of SOX18, microRNA (miR)-204-5p, and cadherin-2 (CDH2) in cells were determined by real-time quantitative polymerase chain reaction and Western blot assay. The interaction of SOX18, miR-204-5p, and CDH2 was analyzed by chromatin immunoprecipitation and dual-luciferase assay. LPS induced HUVECs injury and downregulation of SOX18. SOX18 overexpression increased cell viability, while decreased LDH activity, oxidative stress, and inflammation. SOX18 bound to the miR-204-5p promoter to promote miR-204-5p expression, and further repressed CDH2 expression. miR-204-5p knockdown and CDH2 overexpression abrogated the protective role of SOX18 in HUVECs injury. Overall, SOX18 alleviated LPS-induced injury of HUVECs by promoting miR-204-5p and repressing CDH2, suggesting it as a potential target for sepsis treatment.

Analysis of the Relationship Between MAOA and CDH-13 Genes and Crime

When scholars investigate criminal behaviour, they observe the existence of several criminal organizations characterized by a continuous involvement in illegal activities over successive generations. There is a potential hereditary transmission of criminal conduct. The topic of heredity invariably encompasses the issue of chromosomes and genes, as these elements are essential to the process of heredity. Currently, there is a lack of empirical evidence supporting the notion of criminal genes, and the consensus among scholars in the field of criminal psychology is that criminal behaviour is a multifaceted outcome influenced by physiological, social, and psychological factors. In contemporary times, within the framework of the expeditious advancement of science and technology, there has been a corresponding escalation in the incidence of criminal activities. Researchers have extensively investigated potential connections or shared characteristics among individuals involved in criminal activities across numerous situations. Scientists have directed their attention on genes, seeing them as the fundamental basis of emerging biotechnologies. This research employs a literature review and analysis method to provide a succinct description of the association between the MAOA (Monoamine oxidase A) and CDH-13 (Cadherin-13) genes and criminal behaviour. Furthermore, it examines specific instances to investigate the potential role of genetic factors in contributing to criminal tendencies.

Caffeic Acid Inhibits Proliferation, Migration, and Stemness of DU-145 Prostate Cancer Cells

The issue of toxicity associated with existing cancer drugs necessitates the exploration of the anticancer potentials of natural products such as caffeic acid (CA). Here, we determined the effect of CA on the proliferation, migration, and stem cell-like properties of DU-145 prostate cancer cells. Tetrazolium-based colorimetric assay and flow cytometric analysis showed that CA decreased cell proliferation in a dose- and time-dependent manner without affecting cell cycle progression. CA also inhibited cell migration and repressed epithelial-to-mesenchymal transition by upregulating the expression of cadherin 1 (CDH1) and downregulating the expression of cadherin 2 (CDH2). Furthermore, CA reduced the cancer stem cell population from 95% to 63% and 47% at concentrations of 1.25 and 2.5 mg/mL, respectively; and inhibited stem cell-like properties by downregulating the expression of NANOG and octamer-binding transcription factor 4 (OCT4) genes. These findings suggest that CA could be considered in the development of improved chemotherapy against prostate cancer.

#4387 LIQUID BIOPSY IN PATIENTS TREATED WITH BIOCOMPATIBLE PERITONEAL DIALYSIS FLUIDS – ITS RELATIONSHIP WITH CYTOLOGICAL AND HISTOLOGICAL FINDINGS

Abstract Background and Aims Peritoneal fibrosis can limit long term peritoneal membrane function in peritoneal dialysis (PD) patients. It has been related to bioincompatible PD fluids and peritoneal infections. There are no prospective studies regarding correlation between effluent biomarkers and peritoneal biopsy findings. Our aim was to study the possible relation of peritoneal effluent biomarkers and peritoneal morphology alterations. Method Multicenter prospective study in a cohort of stable PD patients treated with biocompatible PD fluids who received a kidney transplant. We collected in each patient peritoneal biopsy samples and peritoneal effluent fluid. We analyzed the relation between effluent biomarkers, phenotype of mesothelial cells (MC) cultured ex vivo, and peritoneal biopsy parameters (mesothelial integrity, fibrosis and hyalinizing vasculopathy). We compared them with patient characteristics, including peritoneal transport parameters. The biomarkers tested were Collagen-1 (COL-1), Fibronectin (FN), Collagen-13 (COL-13), Interleukin-6 (IL-6), Trombospondin-1, Cadherin 13 (CDH-13), CA-125, Gremlin-1 (GREM-1), Matrix metalloproteinase 2 (MMP-2), CC chemokine ligand 18 (CCL18), Plasminogen activator inhibitor 1 (PAI-1) and Vascular endothelial growth factor A (VEGF-A). Results Forty patients were included (mean age 54.5±15 years, 64% male, 24.1% diabetics). Mean time on PD was 25.5±27 months, 62.1% were on automated PD (APD) and 17.2% had prior peritonitis episodes. A normal MC culture phenotype was observed in 78% of patients. In peritoneal biopsies samples we found partial or total mesothelium preservation in 39%, submesothelial thickness in 42% and vasculopathy in 14% of cases. Effluent PAI-1 levels were significantly lower in patients with mesothelial cell loss than in those with mesothelial preservation (21.62 vs. 38.59 pg/ml respectively; p = 0.031). Patients with peritoneal fibrosis showed significantly higher effluent CDH-13 levels (3.51 vs. 2.32 pg/ml; p = 0.048) and supernatant PAI-1 levels (1183 vs. 72.73; p = 0.000) than those without fibrosis. No other statistical differences were found in other biomarkers analysed. Conclusion Most patients treated with biocompatible peritoneal dialysis fluids showed normal mesothelial cell phenotype in peritoneal effluent culture. Lower PAI-1 effluent levels were associated with mesothelial cell loss and higher effluent CDH-13 levels were related to peritoneal fibrosis.

Goji berry (Lycium barbarum) inhibits the proliferation, adhesion, and migration of oral cancer cells by inhibiting the ERK, AKT, and CyclinD cell signaling pathways: an in-vitro study.

Background: Lycium barbarum (L. barbarum), popularly referred to as Goji berry, is a promising herb known for its powerful anti-antioxidant, antibacterial, and anti-inflammatory properties. It is used in traditional Chinese medicine for treating inflammatory and infectious diseases. It has also shown good anti-cancer properties and has been tested against liver, colon, prostate, breast, and cervical cancers. However, no study has yet evaluated the role of goji berries against oral cancer. Hence, the present paper aims to evaluate the anticancer properties of L. barbarum against oral squamous cell carcinoma. Method: Ethanolic extract of L. barbarum (EELB) was tested for its anticancer properties by performing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, colony formation, cell proliferation, and scratch wound test. The impact of EELB on the signaling transduction pathways of Extracellular signal-regulated kinase (ERK1/2), protein kinase (AKT1), cyclin D1 and epithelial-mesenchymal transition (EMT) was also assessed by western blot. Results: The results showed that EELB can impede CAL-27 cell growth, proliferation and migration in-vitro. It even reduced the phosphorylation of ERK1/2 and AKT1 with concomitant downregulation of cyclin D1 (CCND1), cadherin 2 (CDH2), and vimentin (VIM) and upregulation of cadherin 1 (CDH1) expression suggesting its anti-proliferative and anti-EMT effects in oral cancer. Conclusion: Goji berry has good antiproliferative and anti-invasive properties. It affects potential EMT markers and signaling transduction pathways involved in oral cancers. Hence goji berry can be tried as a potential anticancer agent to manage oral squamous cell carcinoma.

Goji berry (Lycium barbarum) inhibits the proliferation, adhesion, and migration of oral cancer cells by inhibiting the ERK, AKT, and CyclinD cell signaling pathways: an in-vitro study.

Background: Lycium barbarum (L. barbarum), popularly referred to as Goji berry, is a promising herb known for its powerful anti-antioxidant, antibacterial, and anti-inflammatory properties. It is used in traditional Chinese medicine for treating inflammatory and infectious diseases. It has also shown good anti-cancer properties and has been tested against liver, colon, prostate, breast, and cervical cancers. However, no study has yet evaluated the role of goji berries against oral cancer. Hence, the present paper aims to evaluate the anticancer properties of L. barbarum against oral squamous cell carcinoma. Method: Ethanolic extract of L. barbarum (EELB) was tested for its anticancer properties by performing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, colony formation, cell proliferation, and scratch wound test. The impact of EELB on the signaling transduction pathways of Extracellular signal-regulated kinase (ERK1/2), protein kinase (AKT1), cyclin D1 and epithelial-mesenchymal transition (EMT) was also assessed by western blot. Results: The results showed that EELB can impede CAL-27 cell growth, proliferation and migration in-vitro. It even reduced the phosphorylation of ERK1/2 and AKT1 with concomitant downregulation of cyclin D1 (CCND1), cadherin 2 (CDH2), and vimentin (VIM) and upregulation of cadherin 1 (CDH1) expression suggesting its anti-proliferative and anti-EMT effects in oral cancer. Conclusion: Goji berry has good antiproliferative and anti-invasive properties. It affects potential EMT markers and signaling transduction pathways involved in oral cancers. Hence goji berry can be tried as a potential anticancer agent to manage oral squamous cell carcinoma.

Goji berry (Lycium barbarum) inhibits the proliferation, adhesion, and migration of oral cancer cells by inhibiting the ERK, AKT, and CyclinD cell signaling pathways: an in-vitro study.

Background: Lycium barbarum (L. barbarum), popularly referred to as Goji berry, is a promising herb known for its powerful anti-antioxidant, antibacterial, and anti-inflammatory properties. It is used in traditional Chinese medicine due to its powerful antioxidant, antibacterial, and anti-inflammatory properties. It has also shown good anti-cancer properties and has been tested against liver, colon, prostate, breast, and cervical cancers. However, no study has yet evaluated the role of goji berries against oral cancer. Hence, the present paper aims to evaluate the anticancer properties of L. barbarum against oral squamous cell carcinoma. Method: Ethanolic extract of L. barbarum (EELB) was tested for its anticancer properties by performing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, colony formation, cell proliferation, and scratch wound test. The impact of EELB on the signaling transduction pathways of Extracellular signal-regulated kinase (ERK1/2), protein kinase (AKT1), cyclin D1 and epithelial-mesenchymal transition (EMT) was also assessed by western blot. Results: The results showed that EELB can impede CAL-27 cell growth, proliferation and migration in-vitro.. It even reduced the phosphorylation of ERK1/2 and AKT1 with concomitant downregulation of cyclin D1 (CCND1), cadherin 2 (CDH2), and vimentin (VIM) and upregulation of cadherin 1 (CDH1) expression suggesting its anti-proliferative and anti-EMT effects in oral cancer. Conclusion: Goji berry has good antiproliferative and anti-invasive properties. It affects potential EMT markers and signaling transduction pathways involved in oral cancers. Hence goji berry can be tried as a potential anticancer agent to manage oral squamous cell carcinoma.

Hsa_circ_0000119 promoted ovarian cancer development via enhancing the methylation of CDH13 by sponging miR-142-5p.

Ovarian cancer is the leading cause of gynecological cancer-related death in women, and is difficult to treat. The aim of our study is to explore the role and action mechanism of hsa_circ_0000119 in ovarian cancer, thus to analyze whether the circular RNA is a potential target for the treatment of the disease. In this present study, our data shows that hsa_circ_0000119 and DNA methyltransferase 1 (DNMT1) was increased, while miR-142-5p was decreased in ovarian cancer. Overexpression of hsa_circ_0000119 promoted tumor growth, while silencing of hsa_circ_0000119 resulted in an opposite effects. Decreasing of hsa_circ_0000119 also notably inhibited the proliferation, migration, and invasion of the ovarian cancer cells. Moreover, the data proves that hsa_circ_0000119 negatively regulated miR-142-5p and cadherin 13 (CDH13) expression, but positively regulated DNMT1 expression. miR-142-5p could interact with hsa_circ_0000119 and DNMT1 3'-UTR. Silencing of DNMT1 could reverse the inhibition of hsa_circ_0000119 to miR-142-5p and CDH13 expression. Importantly, higher level of CDH13 promoter methylation existed in the ovarian tumors than that in matched normal tissues. DNA methyltransferase inhibitor could increase the expression of CDH13 in ovarian cancer cells. In addition, our results also prove that increasing of CDH13 or miR-142-5p effectively reversed the inhibition of hsa _circ_0000119 to the cell malignant phenotypes. Overall, our data demonstrate that hsa_circ_0000119 facilitated ovarian cancer development through increasing CDH13 expression via promoting DNMT1 expression by sponging miR-142-5p. Our data demonstrate the potential role of hsa_circ_0000119 in the treatment of ovarian cancer.

Genome-wide placental DNA methylations in fetal overgrowth and associations with leptin, adiponectin and fetal growth factors

BackgroundFetal overgrowth “programs” an elevated risk of type 2 diabetes in adulthood. Epigenetic alterations may be a mechanism in programming the vulnerability. We sought to characterize genome-wide alterations in placental gene methylations in fetal overgrowth and the associations with metabolic health biomarkers including leptin, adiponectin and fetal growth factors.ResultsComparing genome-wide placental gene DNA methylations in large-for-gestational-age (LGA, an indicator of fetal overgrowth, n = 30) versus optimal-for-gestational-age (OGA, control, n = 30) infants using the Illumina Infinium Human Methylation-EPIC BeadChip, we identified 543 differential methylation positions (DMPs; 397 hypermethylated, 146 hypomethylated) at false discovery rate < 5% and absolute methylation difference > 0.05 after adjusting for placental cell-type heterogeneity, maternal age, pre-pregnancy BMI and HbA1c levels during pregnancy. Twenty-five DMPs annotated to 20 genes (QSOX1, FCHSD2, LOC101928162, ADGRB3, GCNT1, TAP1, MYO16, NAV1, ATP8A2, LBXCOR1, EN2, INCA1, CAMTA2, SORCS2, SLC4A4, RPA3, UMAD1,USP53, OR2L13 and NR3C2) could explain 80% of the birth weight variations. Pathway analyses did not detect any statistically significant pathways after correcting for multiple tests. We validated a newly discovered differentially (hyper-)methylated gene-visual system homeobox 1 (VSX1) in an independent pyrosequencing study sample (LGA 47, OGA 47). Our data confirmed a hypermethylated gene—cadherin 13 (CDH13) reported in a previous epigenome-wide association study. Adiponectin in cord blood was correlated with its gene methylation in the placenta, while leptin and fetal growth factors (insulin, IGF-1, IGF-2) were not.ConclusionsFetal overgrowth may be associated with a large number of altered placental gene methylations. Placental VSX1 and CDH13 genes are hypermethylated in fetal overgrowth. Placental ADIPOQ gene methylations and fetal circulating adiponectin levels were correlated, suggesting the contribution of placenta-originated adiponectin to cord blood adiponectin.

MiR-495-3p regulates myoblasts proliferation and differentiation through targeting cadherin 2

MircoRNAs (miRNAs) play an important role in skeletal muscle development. Previous study had found that miR-495-3p was differentially expressed in fetal and adult goat skeletal muscle, but its function in myogenic proliferation and differentiation are unclear. Herein, we found the expression of miR-495-3p in C2C12 was downregulated during proliferation stage and upregulated during differentiation stage. Functionally, overexpression of miR-495-3p in C2C12 inhibited proliferation, and promoted myogenic differentiation. Mechanistically, the luciferase reporter assay demonstrated that cadherin 2 (CDH2) was a potential target gene of miR-495-3p. Importantly, overexpression of miR-495-3p inhibited CDH2 expression. Furthermore, knockdown of CDH2 in C2C12 inhibited proliferation and promoted myogenic differentiation. Together, the results showed that miR-495-3p inhibits C2C12 proliferation and promotes myogenic differentiation through targeting CDH2.

In Vitro Effect of Δ9-Tetrahydrocannabinol and Cannabidiol on Cancer-Associated Fibroblasts Isolated from Lung Cancer.

There is evidence that demonstrates the effect of cannabinoid agonists inhibiting relevant aspects in lung cancer, such as proliferation or epithelial-to-mesenchymal transition (EMT). Most of these studies are based on evidence observed in in vitro models developed on cancer cell lines. These studies do not consider the complexity of the tumor microenvironment (TME). One of the main components of the TME is cancer-associated fibroblasts (CAFs), cells that are relevant in the control of proliferation and metastasis in lung cancer. In this work, we evaluated the direct effects of two cannabinoid agonists, tetrahydrocannabinol (THC) and cannabidiol (CBD), used alone or in combination, on CAFs and non-tumor normal fibroblasts (NFs) isolated from adenocarcinoma or from healthy lung tissue from the same patients. We observed that these compounds decrease cell density in vitro and inhibit the increase in the relative expression of type 1 collagen (COL1A1) and fibroblast-specific protein 1 (FSP1) induced by transforming growth factor beta (TGFβ). On the other hand, we studied whether THC and CBD could modulate the interactions between CAFs or NFs and cancer cells. We conditioned the culture medium with stromal cells treated or not with THC and/or CBD and cultured A549 cells with them. We found that culture media conditioned with CAFs or NFs increased cell density, induced morphological changes consistent with EMT, inhibited cadherin-1 (CDH1) gene expression, and induced an increase in the relative expression of cadherin-2 (CDH2) and vimentin (VIM) genes in A549 cells. These changes were inhibited or decreased by THC and CBD administered alone or in combination. In another series of experiments, we conditioned culture media with A549 cells treated or not with THC and/or CBD, in the presence or absence of TGFβ. We observed that culture media conditioned with A549 in the presence of TGFβ induced an increase in the expression of COL1A1 and VIM, both in CAFs and in non-tumor NFs. Both THC and CBD ameliorated these effects. In summary, the results presented here reinforce the usefulness of cannabinoid agonists for the treatment of some relevant aspects of lung cancer pathology, and demonstrate in a novel way their possible effects on CAFs as a result of their relationship with cancer cells. Likewise, the results reinforce the usefulness of the combined use of THC and CBD, which has important advantages in relation to the possibility of using lower doses, thus minimizing the psychoactive effects of THC.

LncRNA MEG3 activates CDH2 expression by recruitment of EP300 in valproic acid-induced autism spectrum disorder

LncRNAs partake in the biological processes contributing to development of autism spectrum disorder (ASD). The aim of the present study is to investigate the effects of lncRNA maternally expressed gene 3 (MEG3) on viability and apoptosis of hippocampal neurons from ASD rats. Rats with ASD were induced using valproic acid (VPA) with normal saline (NS) as control. We performed microarray analysis on hippocampal tissues of NS rats and ASD rats to screen the differentially expressed lncRNAs. MEG3 loss in rats alleviated the impairment of learning and memory abilities induced by VPA, and promoted neuronal viability and inhibited apoptosis. MEG3 could recruit the transcription factor E1A binding protein p300 (EP300) in the nucleus and promote the cadherin 2 (CDH2) expression. CDH2 depletion in rats ameliorated the impairment of learning and memory capacities in ASD rats. After upregulation of CDH2 in neurons with sh-MEG3, we found diminished viability and increased apoptosis in hippocampal neurons of ASD rats. Taken together, MEG3 supports activation of CDH2 via EP300, thus repressing the viability of hippocampal neurons. Therefore, MEG3 upregulation may be partially responsible for the pathogenesis of ASD.

Roles of Cadherin2 in Thyroid Cancer.

BackgroundThe majority of drug-resistant cells in Thyroid cancer (THCA) tend to exhibit an Epithelial mesenchymal transition (EMT) phenotype, and abnormal expression of the cell adhesion molecule Cadherin2 (CDH2) is a hallmark of EMT. However, the roles of CDH2 in THCA and its underlying mechanisms are unknown.MethodsWe analyzed the CDH2 expression in The Cancer Genome Atlas (TCGA) database and screened for genes positively associated with CDH2. Small interfering RNA and cell transfection were used for knocking down CDH2 in THCA cells, cell counting kit-8 (CCK-8) assay and immunofluorescence to detect cell proliferation. Binding miRNAs of CDH2 and CDH2-associated genes were predicted using the Encyclopedia of RNA Interactomes (ENCORI) database. The expression of genes in clinical THCA tissues was investigated from the Human Protein Atlas (HPA) database and validated by qRT-PCR. We conducted the cell functions pathways of CDH2 and CDH2-associated gene FRMD3 by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We also showed the correlation between CDH2 and FRMD3 expression and tumor immune infiltration.ResultsThe expression of CDH2 was significantly higher in THCA tumor tissues compared to normal tissues. Moreover, there were strongly associations of CDH2 expression with the stages T and N. Cellular function assays showed that CDH2 exerted its growth-promoting activity of THCA. To better understand how CDH2 was regulated in THCA, we sought genes associated with CDH2. Correlation analysis revealed that there were negative correlations between genes (CDH2, FRMD3) and miRNAs (hsa-miR-410-3p, hsa-miR-411-5p, hsa-miR-299-5p). Moreover, CDH2 and FRMD3 expression were significantly higher in tumor tissues than in normal tissues, while hsa-miR-410-3p, hsa-miR-411-5p and hsa-miR-299-5p were significantly decreased in tumor tissues compared with normal tissues in THCA. GO and KEEG results showed that CDH2 and FRMD3 were strongly associated with immune-related functions. High expression of CDH2 and FRMD3 was linked to the suppression of immune cells. There were strong negativity correlations between CDH2, FRMD3 and T-cell exhaustion factors.ConclusionOur data indicated that CDH2 and CDH2-related gene FRMD3 might have the critical effects on altering tumors becoming ‘cold tumors’ eventually leading to immune checkpoint inhibitor resistance.

ZEB1 induces N-cadherin expression in human glioblastoma and may alter patient survival.

The present study investigated the expression of epithelial-mesenchymal transition (EMT)-related factors zinc finger E-box-binding homeobox 1 (ZEB1), cadherin-1 (CDH1), cadherin-2 (CDH2) and the cell cycle modulating kinase cyclin-dependent kinase 1 (CDK1) in human glioblastoma (GBM) compared to normal brain tissue, as well as whether the levels of expression were associated with the overall and progression-free survival of the GBM patients. In 44 GBM and five normal brain tissue specimens, the expression levels of ZEB1, CDH1, CDH2 and CDK1 were evaluated by real-time PCR and immunostaining, and the results were correlated with clinical data. The expression levels of all investigated genes as detected by immunostaining were significantly higher in the GBM when compared to the normal brain tissues. There was no influence on survival. A linear correlation between ZEB1 and CDH2 and CDK1 expression was observed in GBM. Moreover, ZEB1 was involved in EMT (e.g., signaling in human GBM) and high ZEB1 levels were linked to an aberrant cell cycle processing, marked by CDK1 overexpression.

Identification of HPCAL1 as a specific autophagy receptor involved in ferroptosis

ABSTRACT Selective macroautophagy/autophagy maintains cellular homeostasis through the lysosomal degradation of specific cellular proteins or organelles. The pro-survival effect of selective autophagy has been well-characterized, but the mechanism by which it drives cell death is still poorly understood. Here, we use a quantitative proteomic approach to identify HPCAL1 (hippocalcin like 1) as a novel autophagy receptor for the selective degradation of CDH2 (cadherin 2) during ferroptosis. HPCAL1-dependent CDH2 depletion increases susceptibility to ferroptotic death by reducing membrane tension and favoring lipid peroxidation. Site-directed mutagenesis aided by bioinformatic analyses revealed that the autophagic degradation of CDH2 requires PRKCQ (protein kinase C theta)-mediated HPCAL1 phosphorylation on Thr149, as well as a non-classical LC3-interacting region motif located between amino acids 46–51. An unbiased drug screening campaign involving 4208 small molecule compounds led to the identification of a ferroptosis inhibitor that suppressed HPCAL1 expression. The genetic or pharmacological inhibition of HPCAL1 prevented ferroptosis-induced tumor suppression and pancreatitis in suitable mouse models. These findings provide a framework for understanding how selective autophagy promotes ferroptotic cell death.Abbreviations: ANXA7: annexin A7; ARNTL: aryl hydrocarbon receptor nuclear translocator like; CCK8: cell counting kit-8; CDH2: cadherin 2; CETSAs: cellular thermal shift assays; CPT2: carnitine palmitoyltransferase 2; DAMP, danger/damage-associated molecular pattern; DPPH: 2,2-diphenyl-1-picrylhydrazyl; DFO: deferoxamine; EBNA1BP2: EBNA1 binding protein 2; EIF4G1: eukaryotic translation initiation factor 4 gamma 1; FBL: fibrillarin; FKBP1A: FKBP prolyl isomerase 1A; FTH1: ferritin heavy chain 1; GPX4: glutathione peroxidase 4; GSDMs: gasdermins; HBSS: Hanks’ buffered salt solution; HMGB1: high mobility group box 1; HNRNPUL1: heterogeneous nuclear ribonucleoprotein U like 1; HPCAL1: hippocalcin like 1; H1-3/HIST1H1D: H1.3 linker histone, cluster member; IKE: imidazole ketone erastin; KD: knockdown; LDH: lactate dehydrogenase; LIR: LC3-interacting region; MAGOH: mago homolog, exon junction complex subunit; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MDA: malondialdehyde; MLKL: mixed lineage kinase domain like pseudokinase; MPO: myeloperoxidase; MTOR: mechanistic target of rapamycin kinase; OE: overexpressing; OSTM1: osteoclastogenesis associated transmembrane protein 1; PRKC/PKC: protein kinase C; PRKAR1A: protein kinase cAMP-dependent type I regulatory subunit alpha; PRDX3: peroxiredoxin 3; PTGS2: prostaglandin-endoperoxide synthase 2; ROS: reactive oxygen species; SLC7A11: solute carrier family 7 member 11; SLC40A1: solute carrier family 40 member 1; SPTAN1: spectrin alpha, non-erythrocytic 1; STS: staurosporine; UBE2M: ubiquitin conjugating enzyme E2 M; ZYX: zyxin