SEARCH · PubMed Health

Results for “Cadherins”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2016

miR-503-3p promotes epithelial-mesenchymal transition in breast cancer by directly targeting SMAD2 and E-cadherin.

Although progress in clinical and basic research has significantly increased our understanding of breast cancer, little is known about the molecular mechanism underlying breast cancer metastasis. Identification of effective therapeutic targets to prevent breast cancer metastasis is urgently needed. The function of miR-503-3p has been investigated in other cancers, but its role in breast cancer remains undefined. Here, we found that miR-503-3p was overexpressed in breast cancer tissue and plasma compared with adjacent normal breast tissue and with plasma from healthy individuals. Moreover, we identified miR-503-3p to be an oncogene of breast cancer cell proliferation, migration and invasion. Upregulation of miR-503-3p in breast cancer cells inhibited expression of epithelial-mesenchymal transition (EMT)-related protein SMAD2 and the epithelial marker protein E-cadherin by directly binding to their mRNA 3' untranslated region, whereas increased expression of mesenchymal marker proteins, including vimentin and N-cadherin. Taken together, our findings support a critical role for miR-503-3p in induction of breast cancer EMT and suggest that plasma miR-503-3p may be a useful diagnostic biomarker for breast cancer.

Base Sequence↗

PubMed2001

Interaction of Galpha 12 and Galpha 13 with the cytoplasmic domain of cadherin provides a mechanism for beta -catenin release.

The G12 subfamily of heterotrimeric G proteins, comprised of the alpha-subunits Galpha12 and Galpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. In an attempt to elucidate specific roles of this subfamily in cell regulation, we sought to identify molecular targets of Galpha12. Here we show a specific interaction between the G12 subfamily and the cytoplasmic tails of several members of the cadherin family of cell-surface adhesion proteins. Galpha12 or Galpha13 binding causes dissociation of the transcriptional activator beta-catenin from cadherins. Furthermore, in cells lacking the adenomatous polyposis coli protein required for beta-catenin degradation, expression of mutationally activated Galpha12 or Galpha13 causes an increase in beta-catenin-mediated transcriptional activation. These findings provide a potential molecular mechanism for the previously reported cellular transforming ability of the G12 subfamily and reveal a link between heterotrimeric G proteins and cellular processes controlling growth and differentiation.

Adenocarcinoma↗

PubMed2017

Surface PD-L1, E-cadherin, CD24, and VEGFR2 as markers of epithelial cancer stem cells associated with rapid tumorigenesis.

Cancer cells require both migratory and tumorigenic property to establish metastatic tumors outside the primary microenvironment. Identifying the characteristic features of migratory cancer stem cells with tumorigenic property is important to predict patient prognosis and combat metastasis. Here we established one epithelial and two mesenchymal cell lines from ascites of a bladder cancer patient (i.e. cells already migrated outside primary tumor). Analyses of these cell lines demonstrated that the epithelial cells with surface expression of PD-L1, E-cadherin, CD24, and VEGFR2 rapidly formed tumors outside the primary tumor microenvironment in nude mice, exhibited signatures of immune evasion, increased stemness, increased calcium signaling, transformation, and novel E-cadherin-RalBP1 interaction. The mesenchymal cells on the other hand, exhibited constitutive TGF-β signaling and were less tumorigenic. Hence, targeting epithelial cancer stem cells with rapid tumorigenesis signatures in future might help to combat metastasis.

B7-H1 Antigen↗

PubMed2000

Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23.

Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafness associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22. Seven highly consanguineous families segregating nonsyndromic autosomal recessive deafness were analyzed to refine the DFNB12 locus. In a single family, a critical region was defined between D10S1694 and D10S1737, approximately 0.55 cM apart. Eighteen candidate genes in the region were sequenced. Mutations in a novel cadherin-like gene, CDH23, were found both in families with DFNB12 and in families with USH1D. Six missense mutations were found in five families with DFNB12, and two nonsense and two frameshift mutations were found in four families with USH1D. A northern blot analysis of CDH23 showed a 9.5-kb transcript expressed primarily in the retina. CDH23 is also expressed in the cochlea, as is demonstrated by polymerase chain reaction amplification from cochlear cDNA.

Alleles↗

PubMed2026

Corrigendum to "miR-503-3p promotes epithelial-mesenchymal transition in breast cancer by directly targeting SMAD2 and E-cadherin" [J. Genet. Genom. (2017) 44, 75-84].

Explore the source record for details and available documents.

Published Erratum↗

PubMed2026

CTGF/CCN2 Promotes Invasive Growth in Cervical Cancer Spheroids and Is Associated With Metastatic Cervical Cancer Tissue.

BACKGROUND/AIM: Metastatic spread defines the lethality of cervical cancer (CC). Connective tissue growth factor (CTGF/CCN2) regulates cell- extracellular matrix interactions but its role in CC is not well-defined. This study investigates the role of CTGF in driving CC invasive growth and its prevalence in patient tissues. MATERIALS AND METHODS: CC spheroids (C33A, HT3) were treated with recombinant human CTGF (rhCTGF) or a function-blocking antibody (IgG CTGF). Invasive growth was assessed via 3D spheroid assay using a Celigo imaging cytometer. Cancer stem cell (CD133, CD44) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin) were analyzed by immunofluorescence. CTGF expression was evaluated using a tissue microarray containing 69 cases in triplicate from pre-invasive, invasive (FIGO I-III), and metastatic cervical lesions, quantified via immunofluorescence scoring. RESULTS: Functional blockade of CTGF significantly reduced 3D spheroid invasive growth in C33A and HT3 cells (p<0.0001). Immunofluorescence revealed that CTGF modulation altered spatial distribution of key proteins: rhCTGF induced surface clustering of CD133 and peripheral N-cadherin enrichment, while CTGF blockade was associated with apparent nuclear/perinuclear enrichment of CD133 and E-cadherin and reduced N-cadherin signal. In patient tissue cores, metastatic samples exhibited the highest CTGF fluorescence intensity. High CTGF expression [immunoreactivity score (IRS) ≥ 6] was most prevalent in FIGO stage I (35.5%) compared to stage III (10.0%). Kaplan-Meier analysis revealed that high CTGF mRNA expression was associated with significantly reduced recurrence-free survival (log-rank p=0.0032). CONCLUSION: In 3D models of CC, CTGF appears to regulate an invasive phenotype, presumably by controlling aberrant localization of stemness and EMT markers. Its apparently elevated expression in early-stage cervical carcinomas and metastases, combined with its prognostic value for recurrence-free survival, suggests that CTGF may be involved in triggering the potential for metastasis and could therefore serve as an early prognostic biomarker.

Humans↗

PubMed2026

Characteristics and functions of a cell adhesion molecule PvCadN in Penaeus vannamei during WSSV infection.

Cell adhesion not only maintains the integrity of the organism, but also plays an important role in the immune system, which is involved in modulation in the interaction between host and virus. In this study, a novel cell adhesion molecule from Penaeus vannamei, designated as PvCadN, was investigated. It had the typical molecular characteristics of cadherin family, with multiple extracellular cadherin repeat domains, a transmembrane region, and a conserved β-catenin-binding motif. Pvcadn is expressed ubiquitously across all detected tissues, with the highest transcriptional level in gills. RNA interference-mediated silencing of pvcadn significantly impaired the adhesion ability of shrimp hemocytes. Upon WSSV infection, pvcadn showed a tissue-specific expression pattern, with upregulation in gills and downregulation in hemocytes. Knockdown of pvcadn markedly suppressed the transcription of WSSV immediate-early gene ie1 and replication of the viral genome in vivo, suggesting that PvCadN acted as a potential virus-associated molecule. Furthermore, it was found that PvCadN was regulated by Lvβ-catenin, a core molecule in the Wnt signaling pathway that functions in innate immunity, at the transcriptional and protein levels. Silencing of lvβ-catenin significantly downregulated pvcadn transcription, and Lvβ-catenin bound directly to the Cadherin C domain of PvCadN. In summary, the study revealed that PvCadN was a key cell adhesion molecule involved in WSSV infection, which was regulated by Lvβ-catenin. Our findings will provide fundamental data for further investigation into cadherin-mediated immune regulation in shrimp, and offer new insights for the prevention and control of WSSV.

Animals↗

PubMed2026

Targeting SUV4-20H2-mediated H4K20 methylation restrains growth and migration in pediatric high-grade astrocytomas.

Pediatric astrocytomas are characterized by increased molecular and clinical heterogeneity with epigenetic alterations contributing to aggressiveness and therapy resistance. The repressive histone mark H4K20 trimethylation (H4K20me3) and the methyltransferase SUV4-20H2 (KMT5C) are critical regulators of chromatin integrity and genome stability, with limited investigation in pediatric astrocytomas. KMT5C mRNA levels were evaluated in a publicly available pediatric gliomas database using bioinformatic analysis. Investigation of SUV4-20H2 and H4K20me3 expression was performed in a cohort of 43 pediatric astrocytoma tissues by immunohistochemistry. Their functional role and mechanism of action was investigated in pediatric glioma cell lines by using the substrate-competitive inhibitor of SUV4-20, A-196. Cell viability, apoptosis and migration were assessed using XTT, cleaved PARP, and wound healing assays, respectively. Effects of treatment on H4K20 methylation, DNA damage, mitotic stress [Polo-like kinase (PLK1) expression], and invasion markers (N-cadherin, β-catenin expression) were examined by western immunoblotting. KMT5C mRNA was significantly enriched in pediatric high-grade astrocytomas compared to low-grade tumors. A significant elevation of SUV4-20H2 and H4K20me3 expression was detected in astrocytoma tissues indicating epigenetic dysregulation contributing to malignancy. Treatment with A-196 reduced cell proliferation of pediatric glioma cell lines and induced apoptosis in a dose-dependent manner. It further impaired cell migration, accompanied by reduced N-cadherin and β-catenin expression. Mechanistically, inhibition of SUV4-20 depleted H4K20me3, inducing chromatin destabilization, replication-associated DNA damage and was associated with increased PLK1 expression, consistent with activation of a mitotic stress response. Our findings indicate that SUV4-20H2-mediated H4K20 activity in pediatric high-grade astrocytomas maintains their growth and migratory potential by regulating chromatin integrity and may serve as potential therapeutic target.

H4K20me2/3↗

PubMed2026

The role of miRNA-32 in non-small cell lung cancer.

BACKGROUND: This study aimed to investigate whether miRNA-32 affects the proliferation and migration of non-small cell lung cancer (NSCLC) cells by regulating the expression of myocyte enhancer factor 2D (MEF2D). METHODS: Quantitative real-time polymerase chain reaction was utilized to evaluate the expression levels of miRNA-32 in clinical NSCLC tissue specimens and cell lines. Western blotting was employed to detect the protein expression levels of MEF2D, E-cadherin, N-cadherin, and CyclinD1, as well as to verify transfection efficiency. Cell proliferation and migration were assessed using Cell Counting Kit-8 and Transwell assays, respectively. Additionally, a dual-luciferase reporter gene assay was performed to validate the targeted regulatory relationship between miRNA-32 and MEF2D. RESULTS: miRNA-32 was significantly downregulated in lung cancer tissues and cell lines, whereas MEF2D exhibited significant upregulation. High miRNA-32 expression correlated with poor clinical outcomes in NSCLC across both our in-house cohort and the TCGA cohort. The stable overexpression of miRNA-32 in lung cancer cells markedly inhibited their proliferation and migratory capabilities. Mechanistically, miRNA-32 inhibited the translation of MEF2D by directly binding to its 3'UTR region. Crucially, the overexpression of MEF2D significantly reversed the inhibitory effects of miRNA-32 on lung cancer cell proliferation and migration. CONCLUSION: The miRNA-32/MEF2D signaling axis plays a pivotal role in the proliferation and metastasis of NSCLC, highlighting its potential as a diagnostic biomarker and prognostic indicator for the disease.

Humans↗

PubMed2026

Transcriptomic Association Between Poliovirus Receptor (PVR/CD155) and Claudin Signaling Pathways in Colorectal Cancer.

BACKGROUND/AIM: Enterotoxigenic Bacteroides fragilis promotes colorectal carcinogenesis through toxin-mediated cleavage of E-cadherin, a process facilitated by membrane-associated Claudin-4 (CLDN4). Separately, the poliovirus receptor (PVR/CD155) modulates tumor epithelial and immune dynamics. This study explored potential transcriptomic interactions and co-expression frameworks between PVR and claudin signaling pathways in colorectal cancer. MATERIALS AND METHODS: Transcriptomic and proteomic data from the The Cancer Genome Atlas-colon adenocarcinoma cohort (TCGA-COAD) were evaluated. An exploratory E-cadherin Cleavage Index was modeled to capture transcript-protein discordance. To control for tissue composition heterogeneity without mathematical circularity, a de-circularized, non-parametric partial rank residual model adjusted for independent CLDN4 expression was deployed within the stable microsatellite-stable (MSS) sub-cohort (N=473). RESULTS: Multivariable survival models showed no independent associations between overall survival and continuous PVR (p=0.79) or CLDN3 (p=0.56) expression. Robust linear modeling revealed no significant baseline interaction between PVR and CLDN4 regarding the exploratory Cleavage Index (p=0.82). However, de-circularized partial correlation analysis revealed a highly stable, positive co-expression between PVR and CLDN3 (rho=0.2459, p=3.23×10-7). Both epithelial markers retained modest inverse correlations with the infiltrating lymphocytic axis (TIGIT and CD96). CONCLUSION: Baseline PVR expression is coordinated with CLDN3 tissue programs independent of general epithelial cellularity but does not interact with the CLDN4 axis or impact overall survival in an unexposed cohort. Because TCGA lacks virome or active microbial exposure tracking, these findings serve as baseline benchmarks for future context-dependent mechanistic studies.

Bacteroides fragilis toxin↗

PubMed2026

Hereditary Diffuse Gastric Cancer With Poorly Differentiated Gallbladder Adenocarcinoma: A Case Report Suggesting Carcinogenesis in the Stomach and Gallbladder Caused by a Pathogenic Germline Variant in CDH1.

BACKGROUND/AIM: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome primarily characterized by a high lifetime risk of diffuse gastric cancer and lobular breast cancer. It is predominantly caused by inactivating germline variants in the tumor suppressor gene CDH1. While the association between HDGC and these two specific malignancies is well-established, the co-occurrence of extra-gastric malignancies in other organs remains exceptionally rare. In particular, the clinical and genetic relationship between HDGC and gallbladder adenocarcinoma has not been previously clarified. CASE REPORT: We present the case of a 67-year-old female initially referred for surgical management of gallbladder cancer (GBC) following an initial cholecystectomy for progressive wall thickening. Pathological examination of the gallbladder revealed a de novo, poorly differentiated adenocarcinoma invading the subserosal layer with reduced E-cadherin expression. Given the atypical histopathology and a significant family history-her father and brother both died of gastric cancer at young ages-a preoperative gastric endoscopy was performed. The endoscopy identified multiple faded mucosal lesions, which biopsy confirmed as signet-ring cell carcinoma. The patient subsequently underwent total gastrectomy and gallbladder bed resection. Postoperative pathology identified 22 distinct malignant gastric lesions, predominantly signet-ring cell carcinoma (pT1a), showing variable or lost E-cadherin expression. Germline genetic testing via direct sequencing identified a pathogenic frameshift mutation in exon 5 of the CDH1 gene. CONCLUSION: This represents the first reported case of synchronous HDGC and primary gallbladder adenocarcinoma associated with a germline CDH1 mutation. Our findings suggest that pathogenic CDH1 variants may contribute to the carcinogenesis of poorly differentiated gallbladder adenocarcinoma. Clinicians should consider the possibility of extra-gastric malignancies in HDGC patients.

Humans↗

PubMed2026

The astragaloside-brucea javanica oil nanoemulsion inhibiting the progression of oral squamous cell carcinoma through CDK1- HOXC10-MTFR2 pathway.

OBJECTIVE: This study aimed to investigate whether Astragaloside-Brucea javanica oil nanoemulsion (AS/BJO-NEs) inhibits the malignant progression of oral squamous cell carcinoma (OSCC) and to further explore its potential regulatory mechanisms. METHODS: Immunohistochemistry (IHC) was used to evaluate the expression of related pathway proteins in human OSCC and adjacent normal tissues. Stable OSCC cell lines with knockdown or overexpression of CDK1/HOXC10 were established. The effects of AS/BJO-NEs and the underlying mechanisms were assessed in vitro through colony formation, wound healing, and Transwell invasion assays, as well as RT-qPCR, western blot, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. An OSCC subcutaneous xenograft model in nude mice was constructed for in vivo validation using RT-qPCR, western blot, hematoxylin and eosin (H&E) staining, and IHC. RESULTS: Analysis of clinical samples revealed upregulated expression of CDK1, P-EZH2, HOXC10, MTFR2, and N-cadherin, alongside downregulated expression of H3K27me3 and E-cadherin in OSCC tissues. In vitro experiments confirmed that AS/BJO-NEs downregulated CDK1 in a concentration-dependent manner, subsequently reducing the expression of P-EZH2, HOXC10, and MTFR2, increasing H3K27me3 levels, and inhibiting cell proliferation, migration, and invasion. H3K27me3 was enriched in the HOXC10 promoter region, and HOXC10 directly bound to and activated MTFR2 transcription. In vivo experiments demonstrated that AS/BJO-NEs effectively inhibited tumor growth, regulated molecules within this pathway and epithelial-mesenchymal transition (EMT) markers, whereas CDK1 overexpression counteracted these effects CONCLUSION: This study demonstrates that AS/BJO-NEs exert anti-OSCC effects by inhibiting CDK1, downregulating HOXC10, thereby reducing MTFR2 expression, and suppressing cell proliferation, migration, invasion, and the EMT process.

Squamous Cell Carcinoma of Head and Neck↗

PubMed2026

Reduced VEPH1 expression is associated with an invasive phenotype and poor prognosis in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) remains a clinically heterogeneous urologic malignancy, and improved biomarkers are needed to refine prognostic stratification. VEPH1 has been implicated in cancer biology, but its role in ccRCC is incompletely defined. This study aimed to investigate the expression, prognostic relevance, and functional effects of VEPH1 in ccRCC. METHODS: VEPH1 transcript expression and prognostic relevance were evaluated using The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) dataset and the University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) and validated in paired ccRCC and adjacent normal renal tissues. The ability of VEPH1 transcript expression to distinguish tumor from normal tissues within the TCGA-KIRC dataset was assessed by receiver operating characteristic analysis. Gain- and loss-of-function experiments were performed in 786-O and 769-P ccRCC cells to determine the effects of VEPH1 on epithelial-mesenchymal transition (EMT)-related markers, migration, and invasion. AKT and ERK phosphorylation was evaluated by western blotting. RESULTS: VEPH1 transcript expression was significantly lower in ccRCC tissues than in normal renal tissues and distinguished tumor from normal samples within the TCGA-KIRC dataset. Low VEPH1 transcript expression was associated with poorer overall survival. Validation in 11 paired clinical specimens confirmed reduced VEPH1 messenger RNA (mRNA) and VEPH1 protein expression in tumor tissues. Functionally, VEPH1 overexpression increased E-cadherin, decreased N-cadherin, and suppressed migration and invasion, whereas partial VEPH1 knockdown produced the opposite changes. In exploratory signaling analyses, VEPH1 overexpression was associated with reduced AKT and ERK phosphorylation without altering total AKT or ERK levels. CONCLUSIONS: Reduced VEPH1 transcript expression was associated with poorer overall survival, whereas experimental VEPH1 depletion was associated with invasive and EMT-related features in ccRCC cells. VEPH1 may represent a candidate prognostic indicator in ccRCC; however, its relationship with AKT and ERK signaling and its clinical relevance require further mechanistic and independent-cohort validation.

Clear cell renal cell carcinoma (ccRCC)↗

PubMed2026

KLK6 is Associated with a Neutrophil-Dominant Immunosuppressive Microenvironment and Epigenetic Deregulation in Lung Adenocarcinoma.

INTRODUCTION: Lung adenocarcinoma (LUAD) is the most prevalent histological subtype of lung cancer and is associated with poor survival despite advances in targeted therapies. Kallikrein-related peptidase 6 (KLK6) has been implicated in several malignancies, but its expression pattern, clinical relevance, and biological function in LUAD remain incompletely characterized. This study aimed to evaluate KLK6 expression and its associations with prognosis, epigenetic regulation, immune infiltration, and migratory phenotypes in LUAD. METHODS: RNA-seq expression and clinical data were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases. KLK6 expression was analyzed in relation to clinicopathological parameters, survival outcomes, promoter methylation status (via UALCAN), and tumor-infiltrating immune cell abundance (via TIMER2.0). In vitro, KLK6 was knocked down using shRNA in A549 and H1299 LUAD cell lines. Cell migration was assessed by transwell assays, and the expression of Epithelial-Mesenchymal Transition (EMT)- and Wnt signaling-related markers was examined by qRT-PCR and Western blotting. RESULTS: KLK6 expression was significantly upregulated in LUAD tissues compared with normal lung tissues. High KLK6 expression was associated with poorer overall survival (HR = 1.52, P = 0.009) and disease-specific survival (HR = 1.55, P = 0.03). ROC analysis showed that KLK6 discriminated stage I LUAD from normal tissues with an AUC of 0.73. Promoter hypomethylation was observed in LUAD tumors and correlated with increased KLK6 expression. Immune infiltration analysis revealed that KLK6-high tumors exhibited reduced B-cell infiltration and increased neutrophil infiltration. Functional experiments demonstrated that KLK6 knockdown significantly suppressed cell migration, accompanied by increased E-cadherin and decreased N-cadherin, Vimentin, Wnt5a, and β-catenin expression. DISCUSSION: These findings suggest that KLK6 overexpression in LUAD is driven in part by promoter hypomethylation and is closely linked to a neutrophil-dominant immunosuppressive microenvironment. Furthermore, KLK6 appears to promote LUAD cell migration through EMT- and Wnt-related signaling pathways. Collectively, these multi-layered data position KLK6 as a potential driver of aggressive tumor behavior and a candidate biomarker for risk stratification. CONCLUSION: KLK6 is aberrantly overexpressed in LUAD and is associated with poor prognosis and enhanced migratory capacity. It may serve as a promising prognostic biomarker and a potential therapeutic target for LUAD.

KLK6↗

PubMed2025

Gut fungi are associated with human genetic variation and disease risk.

Human genetic determinants of the gut mycobiome remain uninvestigated despite decades of research highlighting tripartite relationships between gut bacteria, genetic background, and disease. Here, we present the first genome-wide association study on the number and types of human genetic loci influencing gut fungi relative abundance. We detect 148 fungi-associated variants (FAVs) across 7 chromosomes that statistically associate with 9 fungal taxa. Of these FAVs, several occur in the protein-coding genes PTPRC, ANAPC10, NAV2, and CDH13. Additional FAVs link to tissue-specific gene expression as fungi-associated expression quantitative trait loci. Notably, the relative abundance of gut yeast Kazachstania associates with genetic variation in CDH13 encoding T-cadherin, a protein linked to cardiovascular disease. Kazachstania forms a causal relationship with cardiovascular disease risk in a mendelian two-sample randomization analysis. These findings establish previously unrecognized connections between human genetics, gut fungi, and chronic disease, broadening the paradigm of human-microbe interactions in the gut to the mycobiome.

Humans↗

PubMed2026

Reframing early gastric carcinogenesis through lineage, niche, and evolution.

Early gastric cancer is still commonly conceptualized as the endpoint of a linear sequence from chronic gastritis to intestinal metaplasia, dysplasia, and invasion. Yet recent single-cell, spatial, genomic, and functional studies indicate that this model incompletely captures the biology of early gastric carcinogenesis. Malignant potential is established progressively within a precancerous gastric field already shaped by somatic evolution, chronic inflammatory injury, and epithelial lineage distortion. Within this field, progression is concentrated in a restricted set of precursor states, particularly incomplete, hybrid, and stem-like metaplastic populations that display plasticity, persistence, and increasing compatibility with a supportive microenvironment. Fibroblast niche remodeling, immune protection loss, endothelial rewiring, genomic instability, epigenetic drift, and selective retention of advantageous molecular alterations further promote malignant commitment. In parallel, diffuse gastric cancer appears to follow a distinct route that may arise independently of conventional intestinal metaplasia through E-cadherin-deficient epithelial transformation and downstream chromatin reprogramming. Here, we synthesize recent evidence to propose an updated framework for early gastric carcinogenesis based on field evolution, lineage instability, ecosystem support, and pathway divergence. Rather than replacing the classical Correa cascade, this framework seeks to refine it by shifting the unit of risk assessment from histologic stage alone to biologically defined precursor states shaped by lineage instability, clonal persistence, niche permissiveness, and pathway-specific molecular constraints. This perspective shifts the emphasis of prevention from detecting smaller cancers to identifying and intercepting biologically committed precursor states before invasion occurs.

Humans↗

PubMed2026

The composition of the periostracum in the razor clam Sinonovacula constricta and the mantle's response to sulfide.

The razor clam Sinonovacula constricta inhabits sulfide-rich intertidal sediments and exhibits remarkable tolerance to this toxicant, yet the role of its periostracum in sulfide adaptation remains poorly understood. In this study, we investigated the composition and structure of the periostracum proteins, and the response of the mantle to sulfide stress. Scanning electron microscopy and energy-dispersive X-ray spectroscopy revealed that the periostracum is approximately 10 μm thick and contains 1.43 wt% sulfur, and proteomic analysis further confirmed the presence of organic sulfur (Cys/Met-rich proteins), suggesting its involvement in sulfur deposition. Using LC-MS/MS, we identified 77 high-confidence proteins from the periostracum, which were classified into six functional categories: enzymes, framework proteins, immune-related proteins, calcium ion-related proteins, other proteins, and proteins with unknown functions. Phylogenetic analyses of representative proteins revealed bivalve-specific evolutionary patterns, with several proteins exclusively present in Bivalvia, such as Unknown protein 2 and 7, which possess signal peptides and low-complexity domains. For the sulfide exposure experiment, razor clams were subjected to three Na2S concentrations (0, 10, and 100 μM). qPCR analysis showed that, compared with the control group, Chitin-binding protein 3 and Tyrosinase were significantly upregulated in the mantle, peaking in the 100 μM group at 48 h (5677.84-fold and 157.20-fold, respectively), whereas Collagen and Cadherin 3 were generally suppressed. This study represents one of the most comprehensive proteomic profiles of the razor clam periostracum and highlights the mantle's potential role in sulfide tolerance, offering insights for sulfur-tolerant aquaculture breeding and bioremediation applications.

Animals↗

PubMed2026

Cross-Ancestry Proteogenomic Analyses Identified New Therapeutic Insights for Ischemic Heart Disease.

BACKGROUND: Most drugs target proteins, and proteome-wide genetic analyses in diverse populations could discover potential novel and repurposed targets for improved prevention and treatment of ischemic heart disease (IHD) beyond statin therapy. OBJECTIVES: The purposes of this study were to use cis-acting single nucleotide polymorphisms (cis-pQTLs) identified for plasma proteins in East Asians and Europeans to discover and validate potential drug targets for IHD. METHODS: We measured plasma levels of 9,520 (Olink/SomaScan: 2,923/7,297) proteins in a case-cohort study of IHD (1,976 incident cases and 2,001 subcohort controls) in statin-free individuals in the prospective China Kadoorie Biobank (CKB). Genome-wide association studies identified 2,895 (Olink/SomaScan: 1,301/1,594) cis-pQTLs for these proteins in CKB. Two-sample Mendelian randomization (MR) and colocalization analyses assessed associations of all available cis-pQTLs for these proteins with IHD in East Asians (n = 29,319 cases), with further replication in Europeans (n = 181,522 cases) and comparison with findings in previous MR studies. RESULTS: In CKB observational analyses, a total of 959 (Olink/SomaScan: 426/533) proteins were associated at false discovery rate-corrected P < 0.05 with IHD after adjusting for major IHD risk factors. Two-sample MR analyses provided genetic support for 54 unique (Olink/SomaScan: 36/28) proteins in IHD etiology. Colocalization analyses confirmed shared gene-protein-IHD associations (posterior probability of hypothesis 4 [PPH4] ≥0.8) for 15 unique (Olink/SomaScan: 10/10) proteins, including 8 lipid-related, 3 inflammation-related, 1 blood pressure-related, and 3 alcohol-related proteins in East Asians. In Europeans, MR analyses of 12 non-alcohol-related proteins showed directionally concordant results for 8 proteins, with 5 having strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8), including 4 lipid-related (proprotein convertase subtilisin/kexin type 9, LPA, APOE, cadherin-1) and 1 systolic blood pressure-related (fibroblast growth factor 5) protein. However, 4 proteins showed directionally discordant MR results, including 2 lipid-related (APOA5, SORT1) and 1 inflammation-related (transforming growth factor beta 1) proteins with strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8). Comparison with previous MR studies revealed little consistency across studies in the number and identity of target proteins for IHD beyond well-established lipid-related (low-density lipoprotein cholesterol, lipoprotein(a), and triglycerides) or inflammation-related (interleukin-6) protein targets. CONCLUSIONS: The findings support a role for lipid-driven chronic inflammation in IHD etiology, and treatment strategies simultaneously targeting multiple lipid and inflammation pathways should be prioritized for further research to improve drug treatment of IHD beyond statin therapy.

Aged↗