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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↗
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↗
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

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) &#x2265; 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

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↗
PubMed2025

Long noncoding RNA H19 promotes the acquisition of a mesenchymal-like invasive phenotype in mesothelial primary cells through an HDAC1-mediated WT1/Sp1 switch.

Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in pro-inflammatory conditions, including peritoneal dialysis (PD), a renal replacement therapy. Characteristic of this process is the acquisition of invasive/pro-fibrotic abilities by mesothelial cells (MCs) through induction of mesothelial to mesenchymal transition (MMT), a cell-specific form of EMT. Long noncoding (lnc) RNAs act as major players in physiologic regulatory circuitries of the cell. While LncRNA-H19 (lncH19), one of the first lncRNAs identified, has been broadly studied in tumorigenesis, its role in peritoneum fibrotic diseases has been scarcely addressed so far. Aim of this study was to investigate the role of H19 in the acquisition of a mesenchymal-like phenotype in primary fibrotic MCs from PD patients, and to elucidate epigenetic mechanisms controlling its expression. Genetic silencing/ectopic expression experiments revealed that H19 promoted the expression of MMT markers while downregulating the epithelial marker E-Cadherin, and favored MC directed migration and invasion on a collagen matrix. Silencing of three main H19 isoforms revealed a synergistic activity in the induction of a mesenchymal phenotype. Treatment with MS-275, an HDAC1-3 specific inhibitor previously known to promote MMT reversal, as well as HDAC1 genetic silencing, downregulated lncRNA H19 expression. Bioinformatic analysis revealed a binding sequence of Wilm's Tumor Protein 1 (WT1), the master gene of mesothelial differentiation, on the H19 promoter at an area with multiple acetylation peaks partially overlapping the binding site of Specificity protein 1 (Sp1), another transcription factor active in cellular plasticity regulation. Genetic silencing and Chromatin Immunoprecipitation (ChIP) experiments demonstrated that HDAC1 inhibition promotes a switch between WT1 and Sp1 in H19 promoter occupancy, favoring an inhibitory effect of WT1 on H19 expression and the reversal towards an epithelial-like phenotype. Overall, we discovered an HDAC1-WT1/Sp1-H19 axis potentially relevant to the design of new therapies aimed at counteracting peritoneal fibrosis.

RNA, Long Noncoding↗
PubMed2026

Distal Recirculation of Enteral contents Augmented Mechanically (DREAM) Promotes Intestinal Adaptation and Restores Enterohepatic Signaling in Short Bowel Syndrome.

BACKGROUND & AIMS: Short bowel syndrome (SBS) leads to malabsorption and intestinal failure-associated liver disease. Intestinal adaptation (IA) driven by sustained enteral nutrition (EN) is essential, but EN delivery is limited after major resection. We developed DREAM (Distal Recirculation of Enteral contents Augmented Mechanically), which enables complete EN despite SBS, and enhances IA. We evaluated its efficacy in a translational large-animal model. METHODS: The study randomized 20 neonatal pigs to EN (control), SBS (75% resection), or DREAM. Growth, serum biochemistry, cytokines, intestinal morphology, barrier integrity, hepatic histology, and gene expression (quantitative polymerase chain reaction, RNA sequencing, Kyoto Encyclopedia of Genes and Genomes, and Gene Ontology enrichment) were analyzed. RESULTS: DREAM prevented hepatic and intestinal injury seen in SBS. Serum bilirubin (0.11 vs 5.14 mg/dL, P = .0008), &#x3b3;-glutamyl transferase (23.2 vs 114.6 IU/L, P < .0001), and bile acids (9.7 vs 39 &#x3bc;mol/L, P = .0026) were significantly lower. Inflammatory cytokines (interferon-&#x3b3;, P = .0296; interleukin 1&#x3b2;, P = .0349; and interleukin 6, P = .0189) and portal lipopolysaccharide (P = .0130) markedly improved. DREAM enhanced IA, increasing linear gut density (0.38 vs 0.209 g/cm, P < .0001), villus-to-crypt ratio (P = .0026), glucagon-like peptide 2 (P < .0001) and restored occludin and E-cadherin (P < .001). Hepatic bile salt export pump and cholesterol 7&#x3b1;-hydroxylase regulation were preserved (P = .0373 and P = .0034), and intestinal farnesoid X receptor, Takeda G-protein-coupled receptor 5, and epidermal growth factor signaling were reactivated (P < .01). Transcriptomic analysis confirmed improvements in metabolic, absorptive, and immune pathways. DREAM effluent demonstrated >80% macronutrient absorption within 6 hours (P < .0001). CONCLUSION: DREAM enables full EN in SBS, restoring absorption, mucosal integrity, and gut-liver homeostasis while preventing intestinal failure-associated liver disease. This approach represents a promising translational advance in SBS therapy.

Gut Atrophy↗
PubMed2026

Integrated transcriptomic and functional characterization of Claudin-1 reveals its oncogenic and immunomodulatory roles in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies, driven by its invasive nature and lack of effective biomarkers. Disruption of the epithelial barrier, mediated by tight junction components, is a critical yet underexplored contributor to PDAC progression. Claudins, integral regulators of tight junction integrity, display altered expression across cancers, but their prognostic and immunomodulatory roles in PDAC remain unclear. We performed an integrative analysis of 177 RNA-Seq datasets from TCGA and GTEx to characterize Claudin family alterations in PDAC. Differential expression, copy number variation, methylation, and co-expression networks were analyzed alongside clinical and survival data. Prognostic significance was assessed using Kaplan - Meier and Cox regression analyses, while immune cell infiltration was examined using deconvolution algorithms. Functional validation of Claudin-1 was conducted in Capan-1 cells using CRISPR/Cas9 knockout, followed by proliferation, wound-healing, and Western blot assays. Ten Claudin genes were significantly dysregulated, with Claudin-1 and Claudin-4 frequently amplified and associated with advanced stage and poor survival. High Claudin-1 expression correlated with reduced immune infiltration, indicating an immune-excluded phenotype characterized by immune cells retained in the tumor stroma but largely absent from the tumor parenchyma. Claudin-1 knockout markedly inhibited proliferation, migration, and EMT, evidenced by downregulation of Snail and Slug and restoration of E-cadherin expression. This integrative transcriptomic and functional study identifies Claudin-1 as a key driver of PDAC aggressiveness and immune modulation. These findings establish Claudin-1 as a promising prognostic biomarker and therapeutic target for restoring epithelial integrity and counteracting immune evasion in pancreatic cancer.

Humans↗
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

Scrape Cytology of DEK::AFF2 Fusion-Associated Papillary Squamous Cell Carcinoma of the Sinonasal Tract Masquerading as Schneiderian Papilloma: A Case Report.

INTRODUCTION: DEK::AFF2 fusion-associated papillary squamous cell carcinoma is a recently characterized sinonasal neoplasm that closely mimics Schneiderian papilloma. Although one report has described fine-needle aspiration cytology of a metastatic lymph node, scrape cytological features from the primary site remain undocumented. CASE PRESENTATION: We report the scrape cytology of this tumor in a 26-year-old woman. While certain features (perivascular arrangement and intracytoplasmic nuclear debris-like structures) overlapped with Schneiderian papilloma, several findings diverged: a predominantly discohesive pattern, nuclear enlargement with anisonucleosis, prominent nucleoli, stippled chromatin distinct from the neuroendocrine pattern, and a crackled cytoplasmic appearance. Immunohistochemistry for synaptophysin and chromogranin A was negative, excluding neuroendocrine differentiation. CD163 immunohistochemistry confirmed that the debris-containing cells were not histiocytes. E-cadherin showed heterogeneous downregulation in the initial biopsy, suggesting a candidate molecular basis for the discohesive pattern. The diagnosis was confirmed by AFF2 immunohistochemistry, DEK break-apart fluorescence in situ hybridization, and reverse transcription polymerase chain reaction with Sanger sequencing. Retrospective AFF2 immunohistochemistry of the initial biopsy, originally diagnosed as Schneiderian papilloma, was positive. The patient remained free of disease progression 34 months after completion of chemoradiotherapy for the antecedent lacrimal sac carcinoma. CONCLUSION: These findings provide the first comprehensive cytological documentation of this entity from a primary sinonasal site and delineate features diverging from Schneiderian papilloma that may prompt ancillary investigations.

Case report↗
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

In vitro and in vivo studies on the impact of the familial adenomatous polyposis heterogeneous mutation MUC20-S671C on colorectal carcinogenesis and progression.

BACKGROUND: Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer (CRC). We performed genetic testing on nine FAP patients and identified a recurrent mutation at the 671st site of the MUC20 gene-MUC20-S671C. This mutation has a detection frequency of zero in the 1000 Genomes Project database. Previous studies have demonstrated that MUC20 can promote CRC progression through epithelial-mesenchymal transition (EMT). We conducted a series of experiments to analyze the impact of this mutation on CRC cells, aiming to infer its potential role and significance in CRC patients. METHODS: We introduced the MUC20-S671C mutation into the CRC SW480 cell line using the CRISPR-Cas9 technique and established a stable cell line carrying this mutation. We then conducted various experiments to assess the effects of this mutation. The Transwell assay was used to evaluate cell invasion and migration. We also examined cell proliferation, cell cycle progression, and apoptosis rate. Furthermore, we tested the tumorigenic ability of these cells in NOD-scid IL2R&#x3b3;[null] (NSG) mice. Additionally, transcriptome sequencing was performed on both cell lines and mouse tumor tissues to obtain molecular regulatory network data, and key molecules were further validated. RESULTS: The results of Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and colony formation assays indicated that the proliferation ability of mutant cells was significantly reduced. The Transwell assay demonstrated a marked decline in the invasion and migration capabilities of mutant cells. Flow cytometry analysis revealed that the mutation increased the apoptosis rate of CRC cells and might have caused S-phase arrest. The tumor formation assay in nude mice showed that the tumorigenic ability of mutant cells was weakened. Transcriptome sequencing of both the cells and tumor tissues suggested that the mutation altered the expression of apoptosis- and cell cycle-related molecules and also affected EMT. Further experiments confirmed that key molecules involved in the EMT process, such as E-cadherin, were upregulated, while Vimentin, MMP9, and MMP14 were significantly downregulated, indicating that the mutation weakened the EMT capability of CRC cells. CONCLUSIONS: We have identified a novel mutation, MUC20-S671C, in patients with FAP. Our study demonstrates that this mutation exerts its tumor-suppressive effect by reversing the EMT process.

MUC20-S671C↗
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 &#x3b2;-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↗