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At least 19 recordsLinked to original sources
PubMed2025

Galvanin (TMEM154) is an electric-field sensor for directed cell migration.

Directed cell migration of immune and epithelial cells is critical for their rapid response to tissue injury or infection. Endogenous electric fields generated by disruption of the transepithelial potential across the skin have been postulated to play an important role in guiding cells to wound sites, though how individual cells sense these tissue-scale physical cues remains largely unknown. We have identified Galvanin (TMEM154), a previously uncharacterized single-pass transmembrane protein, as being required for electric-field-guided migration of individual rapidly moving cells. Galvanin functions in both immune and epithelial cell types. Upon exposure of cells to an electric field, Galvanin rapidly relocalizes to the anodal side of a cell, and the net charge on its extracellular domain is necessary and sufficient to drive this spatial relocalization. Furthermore, expression of Galvanin is sufficient to confer electric field-guided migration on otherwise non-responsive epithelial cells. In human neutrophils, we show that Galvanin relocalization is immediately followed by changes in the spatial pattern of cellular protrusion and retraction. The strong directional response of these cells is lost upon truncation of Galvanin's intracellular domain, suggesting that Galvanin acts as a direct sensor of the electric field, transducing spatial information about a cell's electrical environment to the intracellular migratory apparatus. This sensor relocalization mechanism of cell steering defines a new paradigm for directed cell migration.

Journal Article↗
PubMed2026

Furmonertinib inhibits non-small cell lung cancer progression through ANGPT1-mediated regulation of cell migration and apoptosis.

BACKGROUND: Lung cancer remains one of the leading causes of cancer-related mortality worldwide, highlighting the urgent need for effective therapeutic agents. This study investigates the antitumor effects and underlying mechanisms of furmonertinib (FUR) in lung cancer cells. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to identify FUR target genes, followed by functional enrichment, survival, and protein-protein interaction (PPI) network analyses. Human lung cancer cell line A549 was treated with FUR and/or ANGPT1-specific siRNA. Cell migration, apoptosis, and protein expression were assessed by wound healing, flow cytometry, and Western blotting. Cellular thermal shift assay (CETSA) and drug affinity response target stability (DARTS) assays were used to assess FUR-induced stabilization of angiopoietin-1 (ANGPT1) protein. RESULTS: FUR treatment significantly inhibited cell migration and increased apoptosis in NSCLC cells. Bioinformatics analysis revealed 12 overlapping target genes of FUR from the PharmMapper and SwissTargetPrediction databases, with ANGPT1 emerging as a key candidate. ANGPT1 expression was downregulated in tumor tissues and positively correlated with patient survival. Western blotting confirmed that FUR upregulated ANGPT1 protein levels in a dose-dependent manner. Knockdown of ANGPT1 enhanced migration and suppressed apoptosis, while FUR reversed these effects. FUR treatment enhanced the stability of ANGPT1 under high-temperature conditions while reducing its sensitivity to protease. ANGPT1 may have affected tumor cell migration through cell adhesion and extracellular matrix (ECM) pathways. CONCLUSIONS: FUR suppresses lung cancer progression by upregulating ANGPT1, thereby inhibiting cell migration and promoting apoptosis. ANGPT1 is a potential therapeutic target and provides new insights into the anti-tumor mechanism of FUR in lung cancer.

Lung cancer↗
PubMed2026

MX1 promotes gastric cancer cell migration via inhibiting ANXA2 ubiquitination and degradation.

Gastric cancer (GC) is a globally lethal malignancy, with invasion and metastasis driving treatment failure and poor prognosis. MX dynamin like GTPase 1 (MX1) shows tumor-specific functional heterogeneity, while its expression, biological functions and molecular mechanisms in GC remain unclear. Here, we explored MX1's clinical significance and its regulatory mechanism in GC cell migration. We integrated public databases and institutional paired clinical samples for bioinformatics analysis of MX1's correlation with clinical outcomes, and verified its pro-migratory effect via Transwell and wound healing assays. Co-immunoprecipitation/mass spectrometry (Co-IP/MS), immunofluorescence and ubiquitination assays were used to identify MX1-interacting proteins and dissect the underlying mechanism, and the Genomics of Drug Sensitivity in Cancer database was applied for chemosensitivity analysis. MX1 was aberrantly upregulated in GC tissues and served as an independent prognostic biomarker, with high expression associated with shortened overall, first-progression and post-progression survival. MX1 promoted GC cell migration and epithelial-mesenchymal transition pathway enrichment, and directly bound Annexin A2 (ANXA2) in the cytoplasm; both were co-enriched in endothelial and epithelial cells by single-cell sequencing. MX1 dose-dependently upregulated ANXA2 protein (without affecting its mRNA) by inhibiting NEDD4L/TRIM65-mediated ANXA2 ubiquitination and degradation, enhancing ANXA2 stability. Additionally, high MX1 expression correlated with increased paclitaxel sensitivity in GC patients based on database analysis, and CCK-8 assays confirmed that MX1 overexpression significantly reduced the paclitaxel IC50 in gastric cancer cells, supporting its potential as a predictive biomarker for paclitaxel efficacy. This study demonstrates that MX1 promotes GC cell migration by suppressing ANXA2 ubiquitination and degradation, highlighting the critical role of the MX1-ANXA2 axis in GC progression. These findings provide novel molecular targets and theoretical support for GC prognostic evaluation, individualized chemotherapy and targeted therapy.

ANXA2↗
PubMed2025

Nuclear rupture in confined cell migration triggers nuclear actin polymerization to limit chromatin leakage.

Upon cell migration in confined space, such as during cancer metastasis, mechanical forces from the extracellular matrix act onto the nucleus leading to nuclear envelope (NE) rupture, chromatin leakage and genomic instability. Here we found that during confined migration, NE rupture triggers dynamic nuclear F-actin formation dependent on the formins DIAPH1 and DIAPH3. We show that DIAPH3 dynamically and transiently relocates to the nucleus upon NE rupture. Interfering with DIAPH1/3 or with nuclear actin polymerization resulted in nuclear instability during confined migration. Notably, nuclear formin activity or actin assembly limit NE rupture-induced chromatin leakage. Similarly, silencing of Ataxia Telangiectasia and Rad3-related protein (ATR) reduced NE rupture-triggered nuclear F-actin assembly and increased chromatin leakage. Consistent with this, ATR promotes the phosphorylation of DIAPH3 at S1072 adjacent to its autoregulatory domain to promote nuclear actin polymerization. Using atomic force microscopy, we found that nuclear actin assembly or nuclear DIAPH3 activity promotes nuclear stiffness in an ATR-dependent manner. Thus, our study identifies an ATR-formin module that regulates nuclear mechanical properties through induction of intranuclear actin scaffolding.

Formins↗
PubMed2026

Expression of PIEZO1 in lung adenocarcinoma correlates with PD-L1 expression, cell migration, and poor prognosis: an exploratory study.

BACKGROUND AND AIMS: Lung adenocarcinoma (LUAD) treatment is challenging process. and the function of PIEZO1, a mechanically sensitive ion channel has not been systematically determined. In this study we aimed to explore the expression, potential associations, and clinical significance of PIEZO1 in LUAD. METHODS AND AIMS: A comprehensive bioinformatics analysis was performed using data from the Cancer Genome Atlas (TCGA) database, the Gene Expression Omnibus (GEO) database and other databases. Experimental validation was performed to confirm the expression patterns and preliminarily examine the associations of PIEZO1 in LUAD cell lines. RESULTS: PIEZO1 expression was significantly lower in LUAD tissues than in normal lung tissues (P&#x2009;<&#x2009;0.05). Its expression was correlated with advanced pathological stage, lymph node involvement, and distant metastasis. High PIEZO1 expression was associated with a distinct immune-related tumor microenvironment, characterized by correlations with the expression levels of multiple immune checkpoint molecules, and was identified as an independent factor associated with poor overall survival (HR&#x2009;=&#x2009;1.49; 95% CI 1.11-2; P&#x2009;<&#x2009;0.007). In vitro experiments confirmed the downregulated PIEZO1 expression in LUAD cell lines, and functional knockdown experiments revealed its association with cell migration and PD-L1 expression. CONCLUSION: This exploratory study revealed that PIEZO1 expression in LUAD cell lines correlated with the expression of immune-related features and EMT-related genes, as well as poor prognosis. In vitro, PIEZO1 knockdown is associated with reduced cell migration and decreased PD-L1 expression. These findings provide a basis for future investigations into the potential role of PIEZO1 in LUAD.

Gene expression↗
PubMed2025

An intermediate activation state primes Langerhans cell migration from the epidermis.

Langerhans cells (LCs) are a specialized subset of dendritic cells in the epidermis, forming a dense network that acts as a frontline defense through immune surveillance. Upon antigen uptake, LCs become activated and orchestrate subsequent immune responses by migrating to lymphatics. However, how transcriptional programs are regulated during activation and how LCs behave in vivo during this transition remain poorly understood. Here, we combine single-cell transcriptomic analysis and intravital imaging to reconstruct the activation trajectory of epidermal LCs. We present a high-resolution single-cell transcriptomic dataset of over 22,000 high-quality epidermal LCs in both homeostatic and injured conditions. We define specific LC subpopulations representing sequential activation stages, characterized at the level of pathways and transcription factors. Notably, we identify a distinct intermediate state that precedes their migration. Integrating our data with an external dataset from homeostatic and injured skin reveals that wound-specific, WNT-modulated fibroblasts are the primary source of C3, the central component of the complement cascade. Intravital imaging of C3-deficient mice demonstrated that C3 is essential for effective recruitment of activated LCs to wound sites. Together, our findings uncover a novel population of activated epidermal LCs and highlight complement signaling as a critical mediator of LC recruitment during skin injury.

Activation↗
PubMed2026

Proteomic profiling reveals that DPP4 overexpression increases cell adhesion, inhibits cell migration, and restores androgen sensitivity in prostate cancer.

Dipeptidyl peptidase-4 (DPP4), a serine protease with both enzymatic and non-enzymatic roles, has emerged as a context-dependent modulator of tumor progression. In the present study, we investigated the expression and function of DPP4 in androgen-sensitive and castration-resistant prostate cancer (CRPC) models. Proteomic analysis of androgen-resistant prostate cells overexpressing DPP4 identified the involvement of the cellular adhesion molecules pathway. In prostate cells, lentiviral-mediated DPP4 overexpression restored androgen receptor signaling, inhibited epithelial-to-mesenchymal transition, and reduced cell migration, whereas DPP4 silencing produced the opposite effects. We demonstrate that DPP4 expression is down-regulated in CRPC cells and that treatment with capsaicin (CAP), a bioactive compound derived from red peppers, restores DPP4 expression. Moreover, DPP4 restoration by CAP suppresses prostate tumorigenesis in the TRAMP mice in vivo model of prostate cancer. Our results suggest that DPP4 could be a new target for CRPC.

Male↗
PubMed2026

Impaired stem cell migration and divisions in Duchenne muscular dystrophy revealed by live imaging.

Dysregulation of stem cell properties is a hallmark of many pathologies, but the dynamic behaviour of stem cells in their microenvironment during disease progression remains poorly understood. Using the mdx mouse model of Duchenne Muscular Dystrophy, we developed innovative live imaging of muscle stem cells (MuSCs) in vivo, and ex vivo on isolated myofibres. We show that mdx MuSCs have impaired migration and precocious differentiation through unbalanced symmetric divisions, driven by p38 and PI3K signalling pathways, in contrast to the p38-only dependence of healthy MuSCs. Cross-grafting shows that MuSC fate decisions are governed by fibre-independent cues, whereas their migration behaviour is determined by the myofibre niche. This study provides the first dynamic analysis of dystrophic MuSC properties in vivo, reconciling conflicting reports on their function. Our findings establish DMD as a MuSC disease with niche dysfunctions, offering strategies to restore stem cell functions for improved muscle regeneration.

Stem Cells↗
PubMed2026

Oncogenic PIK3CA enhances collective migration of mammary epithelial cells through ERK wave propagation.

Oncogenic mutations of the PIK3CA gene, which encodes the catalytic subunit of the phosphatidylinositol 3-kinase (PI3K) enhance cell migration via ERK (ERK1 and ERK2, also known as MAPK3 and MAPK1, respectively) activation. We analyzed the factors regulating collective cell migration (CCM) of genome-edited MCF10A cell lines carrying hotspot PIK3CA mutations E545K or H1047R. H1047R enhanced CCM and promoted the propagation of waves of ERK activity backwards from the wound edge, whereas E545K impaired both coordinated CCM and ERK activity wave formation. The distance traveled by ERK activity waves correlated with directional persistence of migrating cells. Inhibition of cell contractility stimulated ERK wave propagation and efficient CCM of E545K cells but impaired ERK waves and CCM in control cells. Impaired ERK wave propagation was consistently associated with non-linear cell-cell junctions and the loss of polarized distribution of actomyosin. Taken together, these analyses suggest that polarized actomyosin contractility and pulsatile ERK activation must be constrained in the territory of a phase diagram compatible with mechanotransduction of ERK waves across cell-cell junctions to achieve highly coordinated and efficient collective migration.

Cell Movement↗
PubMed2022

WNK1-OSR1 Signaling Regulates Angiogenesis-Mediated Metastasis towards Developing a Combinatorial Anti-Cancer Strategy.

Lysine-deficient protein kinase-1 (WNK1) is critical for both embryonic angiogenesis and tumor-induced angiogenesis. However, the downstream effectors of WNK1 during these processes remain ambiguous. In this study, we identified that oxidative stress responsive 1b (osr1b) is upregulated in endothelial cells in both embryonic and tumor-induced angiogenesis in zebrafish, accompanied by downregulation of protein phosphatase 2A (pp2a) subunit ppp2r1bb. In addition, wnk1a and osr1b are upregulated in two liver cancer transgenic fish models: [tert x p53-/-] and [HBx,src,p53-/-,RPIA], while ppp2r1bb is downregulated in [tert x p53-/-]. Furthermore, using HUVEC endothelial cells co-cultured with HepG2 hepatoma cells, we confirmed that WNK1 plays a critical role in the induction of hepatoma cell migration in both endothelial cells and hepatoma cells. Moreover, overexpression of OSR1 can rescue the reduced cell migration caused by shWNK1 knockdown in HUVEC cells, indicating OSR1 is downstream of WNK1 in endothelial cells promoting hepatoma cell migration. Overexpression of PPP2R1A can rescue the increased cell migration caused by WNK1 overexpression in HepG2, indicating that PPP2R1A is a downstream effector in hepatoma. The combinatorial treatment with WNK1 inhibitor (WNK463) and OSR1 inhibitor (Rafoxanide) plus oligo-fucoidan via oral gavage to feed [HBx,src,p53-/-,RPIA] transgenic fish exhibits much more significant anticancer efficacy than Regorafenib for advanced HCC. Importantly, oligo-fucoidan can reduce the cell senescence marker-IL-1&#x3b2; expression. Furthermore, oligo-fucoidan reduces the increased cell senescence-associated &#x3b2;-galactosidase activity in tert transgenic fish treated with WNK1-OSR1 inhibitors. Our results reveal the WNK1-OSR1-PPP2R1A axis plays a critical role in both endothelial and hepatoma cells during tumor-induced angiogenesis promoting cancer cell migration. By in vitro and in vivo experiments, we further uncover the molecular mechanisms of WNK1 and its downstream effectors during tumor-induced angiogenesis. Targeting WNK1-OSR1-mediated anti-angiogenesis and anti-cancer activity, the undesired inflammation response caused by inhibiting WNK1-OSR1 can be attenuated by the combination therapy with oligo-fucoidan and may improve the efficacy.

Animals↗
PubMed2025

Putative function and prognostic molecular marker of mast cells in colorectal cancer.

BACKGROUND: The increased demand for markers for colorectal cancer (CRC) highlights the importance of investigating immune cells involved in CRC progression. This study aims to dissect the mast cells in CRC, characterize the role of mast cells in CRC development, coordinate molecular communication between mast cells and malignant cells, and construct and validate a prognostic classification model based on mast cell markers. METHODS: Single-cell transcriptome data of CRC patients were extracted from GSE146771 for cell classification and annotation. The malignant cells were identified by copykat and the communication between mast cells and malignant cells was analyzed by CellChat. Least absolute shrinkage and selection operator (LASSO) regression analysis and Cox regression analysis of mast cell markers were performed in the TCGA-COAD cohort to construct a prognostic classification model. qRT-PCR was performed to detect the mRNA expression of the molecules in the classification model in P815 and MC-9 cells. The co-culture experiment of MC38 and P815 cells&#xa0;were performed in 12-well transwell dish. Wound healing assay and Transwell assay were performed to detect cell migration and invasion. RESULTS: 10,186 high-quality cells in GSE146771 were annotated to 9&#xa0;cell types. Six markers in mast cells (HDC, GATA2, ASAH1, BTBD19, TIMP1, FAM110A) were selected to construct a classification model. The high-risk score defined showed high infiltration of immunosuppressive cells, including endothelial cells, CAFs, Tregs and high angiogenesis and epithelial-mesenchymal transition (EMT) activities. In the model, HDC were abnormally low expressed in P815 cells, while BTBD19, FAM110A, GATA2, ASAH1 and TIMP1 showed excessive expression in P815 cells. Knockdown of GATA2 in the co-culture system of P815 and MC38 cells&#xa0;blocked cell migration and invasion. CONCLUSION: This study identified the cell types within CRC, elaborated the cellular functions of mast cells in CRC development and their molecular communication to coordinate malignant cells, and highlighted the molecular components and biological features that constitute promising prognostic classification model.

Mast Cells↗
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↗
PubMed2025

SISTEM: simulation of tumor evolution, metastasis, and DNA-seq data under genotype-driven selection.

SUMMARY: SISTEM is a software package and mathematical framework for simulating tumor evolution and cell migrations at single-cell resolution. Unlike existing frameworks which simulate cancer cell populations under the neutral coalescent or using simple birth-death models, SISTEM simulates tumor populations under somatic clonal selection using an agent-based framework. SISTEM can generate mutation profiles, read counts, and DNA sequencing reads along with ground truth cell lineages and migration graphs under a number of easily customizable mutation and selection models. For improved realism, SISTEM allows for cell fitness to be driven by genomic events of various scales including single nucleotide variants, segmental gains and losses, whole-chromosomal and chromosome-arm aberrations, and whole-genome duplications. SISTEM also includes numerous migration models to simulate metastatic cancers, facilitating the exploration and evaluation of diverse migration patterns. AVAILABILITY AND IMPLEMENTATION: SISTEM is written in Python and is freely available open-source under GNU GPLv3 from: https://github.com/samsonweiner/sistem.

Software↗
PubMed2026

Integrative Multi-Omics Analysis Identifies Thrombosis-Associated Molecular Features Linked to Germline Susceptibility and Immune Cell Communication in Gastric Cancer.

Emerging evidence indicates that coagulation-related molecular programs are associated with thrombosis, tumor progression, and molecular dysregulation in gastric cancer (GC). However, thrombosis-associated molecular features in GC and their potential links to inherited susceptibility remain insufficiently understood. Integrated analyses of transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were performed to identify thrombosis-associated genes and establish a machine learning-based prognostic signature. Genome-wide association study (GWAS), expression quantitative trait loci (eQTL), transcriptome-wide association study (TWAS), and Mendelian randomization (MR) analyses were conducted to investigate susceptibility-associated transcriptional programs in GC. Functional assays were used to evaluate candidate genes associated with malignant phenotypes. Single-cell RNA sequencing (scRNA-seq) and cell-cell communication analyses were further performed to characterize cell-type-specific expression patterns and potential intercellular interactions. A total of 22 differentially expressed thrombosis-associated genes were identified, and a prognostic signature comprising 14 genes was established. The signature stratified patients into high- and low-risk groups and showed prognostic performance in both the training and validation cohorts. Integrative GWAS, eQTL, and TWAS analyses identified susceptibility-associated transcriptional programs that were positively correlated with the thrombosis-associated risk score. Silencing ACTN2 and CRYAB significantly reduced GC cell migration and invasion. scRNA-seq analysis revealed relatively high CRYAB expression in neutrophils, and CellChat analysis suggested potential neutrophil-B cell interactions involving COLLAGEN-related signaling. This integrative multi-omics study identified a thrombosis-associated molecular signature linked to prognosis and germline susceptibility-associated transcriptional programs in GC. ACTN2 and CRYAB may represent candidate genes associated with GC cell migration and invasion, while single-cell analysis suggested potential immune-related communication features.

Humans↗
PubMed2025

A Modular Platform for the Optogenetic Control of Small GTPase Activity in Living Cells Reveals Long-Range RhoA Signaling.

Small GTPases are critical regulators of cellular processes, such as cell migration, and comprise a family of over 167 proteins in the human genome. Importantly, the location-dependent regulation of small GTPase activity is integral to coordinating cellular signaling. Currently, there are no generalizable methods for directly controlling the activity of these signaling enzymes with subcellular precision. To address this issue, we introduce a modular, optogenetic platform for the spatial control of small GTPase activity within living cells, termed spLIT-small GTPases. This platform enabled spatially precise control of cytoskeletal dynamics such as filopodia formation (spLIT-Cdc42) and directed cell migration (spLIT-Rac1). Furthermore, a spLIT-RhoA system uncovered previously unreported long-range RhoA signaling in HeLa cells, resulting in bipolar membrane retraction. These results establish spLIT-small GTPases as a versatile platform for the direct, spatial control of small GTPase signaling and demonstrate the ability to uncover spatially defined aspects of small GTPase signaling.

Journal Article↗
PubMed2022

Heterozygous Tropomodulin 3 mice have improved lung vascularization after chronic hypoxia.

The molecular mechanisms leading to high-altitude pulmonary hypertension (HAPH) remains poorly understood. We previously analyzed the whole genome sequence of Kyrgyz highland population and identified eight genomic intervals having a potential role in HAPH. Tropomodulin 3 gene (TMOD3), which encodes a protein that binds and caps the pointed ends of actin filaments and inhibits cell migration, was one of the top candidates. Here we systematically sought additional evidence to validate the functional role of TMOD3. In-silico analysis reveals that some of the SNPs in HAPH associated genomic intervals were positioned in a regulatory region that could result in alternative splicing of TMOD3. In order to functionally validate the role of TMOD3 in HAPH, we exposed Tmod3-/+ mice to 4&#xa0;weeks of constant hypoxia, i.e. 10% O2 and analyzed both functional (hemodynamic measurements) and structural (angiography) parameters related to HAPH. The hemodynamic measurements, such as right ventricular systolic pressure, a surrogate measure for pulmonary arterial systolic pressure, and right ventricular contractility (RV-&#x2009;&#xb1;&#x2009;dP/dt), increases with hypoxia did not separate between Tmod3-/+ and control mice. Remarkably, there was a significant increase in the number of lung vascular branches and total length of pulmonary vascular branches (P&#x2009;<&#x2009;0.001) in Tmod3-/+ after 4&#xa0;weeks of constant hypoxia as compared with controls. Notably, the Tmod3-/+ endothelial cells migration was also significantly higher than that from the wild-type littermates. Our results indicate that, under chronic hypoxia, lower levels of Tmod3 play an important role in the maintenance or neo-vascularization of pulmonary arteries.

Actin Cytoskeleton↗
PubMed2025

Abnormal levels of miRNA in pancreatic cancer are linked to tumor progression by regulating the translation of tumor-associated mRNA.

BACKGROUND: Pancreatic cancer remains one of the most malignant tumors, characterized by limited treatment efficacy. MAIN FINDINGS: microRNAs (miRNAs) play a crucial role in regulating the proliferation, invasion, migration, drug resistance, apoptosis, and cell cycle progression of pancreatic cancer cells by inhibiting tumor-associated proteins. Metscape analysis revealed that miRNA-targeted proteins associated with pancreatic cancer are enriched in processes such as cell proliferation, mitosis, and cell migration, and participate in multiple signaling pathways. These proteins primarily localize to classical pathways, including JAK/STAT, PI3K/AKT, and Wnt/&#x3b2;-catenin. Furthermore, gene mutations or abnormal alternative poly(A)denylation (APA) within miRNA-targeted regions can disrupt base pairing to the 3'-Untranslated Region (3'-UTR), thereby enhancing the translation of oncogenic mRNA translation. FUTURE DIRECTIONS: Collectively, these findings indicate that multiple miRNAs act cooperatively to influence pancreatic cancer progression. Consequently, therapeutic strategies aimed at restoring the balance of the miRNA system are essential to disrupt the 'mRNA-oncogene' vicious cycle.

Humans↗