The Role of TGF-β/SMAD Signaling in Hepatocellular Carcinoma: from Mechanism to Therapy and Prognosis

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(4), P. 1436 - 1451

Published: Jan. 1, 2024

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with high incidence and mortality, accounting for approximately 90% liver cancer.The development HCC a complex process involving abnormal activation or inactivation multiple signaling pathways.Transforming growth factor-β (TGF-β)/Small mothers against decapentaplegic (SMAD) pathway regulates HCC.TGF-β activates intracellular SMADs protein through membrane receptors, resulting in series biological cascades.Accumulating studies have demonstrated that TGF-β/SMAD plays regulatory functions HCC.However, there still controversy about role HCC.Because it involves different pathogenic factors, disease stages, cell microenvironment, as well upstream downstream relationships other pathways.This review will summary mechanism HCC, regulation populations, microenvironments, interaction microRNAs.In addition, we also introduced small molecule inhibitors, therapeutic vaccines, traditional Chinese medicine extracts based on targeting pathway, which provide future research direction therapy pathway.

Language: Английский

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Molecular mechanisms in colitis-associated colorectal cancer

Oncogenesis, Journal Year: 2023, Volume and Issue: 12(1)

Published: Oct. 26, 2023

Abstract Sustained chronic inflammation of the large intestine leads to tissue damage and repair, which is associated with an increased incidence colitis-associated colorectal cancer (CAC). The genetic makeup CAC somewhat similar sporadic carcinoma (sCRC), but there are differences in sequence timing alterations carcinogenesis process. Several models have been developed explain development CAC, particularly “field cancerization” model, proposes that accelerates mutagenesis selects for clonal expansion phenotypically normal, pro-tumorigenic cells. In contrast, “Big Bang” model posits tumorigenic clones multiple driver gene mutations emerge spontaneously. details tumorigenesis—and how they differ from sCRC—are not yet fully understood. this Review, we discuss recent genetic, epigenetic, environmental findings related pathogenesis past five years, a focus on unbiased, high-resolution profiling non-dysplastic field cancerization context inflammatory bowel disease (IBD).

Language: Английский

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SMAD Proteins in TGF-β Signalling Pathway in Cancer: Regulatory Mechanisms and Clinical Applications

Diagnostics, Journal Year: 2023, Volume and Issue: 13(17), P. 2769 - 2769

Published: Aug. 26, 2023

Suppressor of mother against decapentaplegic (SMAD) family proteins are central to one the most versatile cytokine signalling pathways in metazoan biology, transforming growth factor-β (TGF-β) pathway. The TGF-β pathway is widely known for its dual role cancer progression as both an inhibitor tumour cell and inducer metastasis. This mainly mediated through SMAD their cofactors or regulators. act transcription factors, regulating a wide range genes, rich post-translational modifications influenced by variety regulators cofactors. complex role, mechanisms, important functions tumours hot topics current oncology research. In this paper, we summarize recent progress on effects mechanisms development, diagnosis, treatment prognosis, provide clues subsequent research tumours.

Language: Английский

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Periodontitis increases the risk of gastrointestinal dysfunction: an update on the plausible pathogenic molecular mechanisms

Critical Reviews in Microbiology, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 31

Published: April 11, 2024

Periodontitis is an immuno-inflammatory disease of the soft tissues surrounding teeth. linked to many communicable and non-communicable diseases such as diabetes, cardiovascular disease, rheumatoid arthritis, cancers. The oral-systemic link between periodontal systemic attributed spread inflammation, microbial products microbes distant organ systems. Oral bacteria reach gut via swallowed saliva, whereby they induce dysbiosis gastrointestinal dysfunctions. Some pathogens like Porphyromonas. gingivalis, Klebsiella, Helicobacter. Pylori, Streptococcus, Veillonella, Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus, Haemophilus, Aggregatibacter actinomycetomcommitans Streptococcus mutans can withstand unfavorable acidic, survive in result dysbiosis. Gut increases dysplastic changes that lead dysfunction. Various studies have oral bacteria, oral-gut axis various GIT disorders inflammatory bowel liver diseases, hepatocellular pancreatic ductal carcinoma, ulcerative colitis, Crohn's disease. Although correlation periodontitis well established, intricate molecular mechanisms by which microflora these not been discussed extensively. This review comprehensively discusses unique immunological

Language: Английский

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Transforming Growth Factor Beta Promotes Inflammation and Tumorigenesis in Smad4‐Deficient Intestinal Epithelium in a YAP‐Dependent Manner

Advanced Science, Journal Year: 2023, Volume and Issue: 10(23)

Published: June 1, 2023

Transforming growth factor beta (TGF-β), a multifunctional cytokine, plays critical roles in immune responses. However, the precise role of TGF-β colitis and colitis-associated cancer remains poorly defined. Here, it is demonstrated that promotes colonic inflammation related tumorigenesis absence Smad family member 4 (Smad4). Smad4 loss intestinal epithelium aggravates neoplasia induced by dextran sulfate sodium (DSS) azoxymethane/dextran (AOM/DSS), leading to over-activated responses increased TGF-β1 levels. In Smad4-deficient organoids, stimulates spheroid formation impairs stem cell proliferation lineage specification. YAP, whose expression directly upregulated after deletion, mediates effect interacting with Smad2/3. Attenuation YAP/TAZ prevents TGF-β1-induced Smad4-/- organoids alleviates mice. Collectively, these results highlight an integral TGF-β/Smad4 axis restraining suggest or YAP signaling as therapeutic targets for gastrointestinal diseases intervention.

Language: Английский

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Interactions between NAD+ metabolism and immune cell infiltration in ulcerative colitis: subtype identification and development of novel diagnostic models

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 5, 2025

Ulcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa with increasing incidence worldwide. Growing evidence highlights pivotal role nicotinamide adenine dinucleotide (NAD+) metabolism in UC pathogenesis, prompting our investigation into subtype-specific molecular underpinnings and diagnostic potential NAD+ metabolism-related genes (NMRGs). Transcriptome data from patients healthy controls were downloaded GEO database, specifically GSE75214 GSE87466. We performed unsupervised clustering based on differentially expressed (DE-NMRGs) to classify cases distinct subtypes. GSEA GSVA identified biological pathways active within these subtypes, while CIBERSORT algorithm assessed differential immune cell infiltration. Weighted gene co-expression network analysis (WGCNA) combined expression was used pinpoint specific NMRGs UC. Robust features for subtyping diagnosis selected using two machine learning algorithms. Nomograms constructed their effectiveness evaluated receiver operating characteristic (ROC) curves. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) conducted verify lines. In study, classified subtypes DE-NMRGs levels, Cluster A exhibiting enhanced self-repair capabilities during responses B showing greater inflammation tissue damage. Through comprehensive bioinformatics analyses, we four key biomarkers (AOX1, NAMPT, NNMT, PTGS2) subtyping, (NNMT, PARP9) its diagnosis. These are closely linked various cells microenvironment, particularly NAMPT PTGS2, which strongly associated neutrophil developed demonstrated high predictive accuracy, achieving area under curve (AUC) values up 0.989 0.997 training set 0.998 0.988 validation sets. RT-qPCR showed significant upregulation NNMT PARP9 inflamed versus normal epithelia, underscoring relevance. Our study reveals UC, identifying findings could suggest therapeutic targets contribute advancing personalized treatment strategies potentially improving patient outcomes.

Language: Английский

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Gene expression regulation and polyadenylation in ulcerative colitis via long-chain RNA sequencing

BMC Genomics, Journal Year: 2025, Volume and Issue: 26(1)

Published: Feb. 15, 2025

Ulcerative colitis (UC) is an immune-mediated chronic intestinal disease, with a pathogenesis that remains incompletely understood. The purpose of this study to analyze the difference gene expression between UC patients and healthy controls using Oxford Nanopore Technology's long-read RNA sequencing (ONT-RNA-seq) explore how alternative polyadenylation (APA) site selection contributes pathogenesis. Colon tissue samples from normal (NC) were collected, total was extracted sequenced ONT-RNA-seq technology. Various bioinformatics analyses performed, including differential (DEG) analysis, functional enrichment APA prediction miRNAs binding proteins (RBPs) targets, molecular mechanism underlying UC. analysis revealed levels ACSF2, NPY, SLC26A3, BRINP3, PKLPP2 significantly lower in compared NC group, while CCL20, CCL21, CD55, IDO1, LCN2, NOS2, CCL11, OLFM4, ANXA1, REG1A, S100A9, SLPI, SPINK1, AGR2 higher. Functional showed DEGs closely related immune inflammatory responses, which turn are many challenges diagnosis treatment Mechanistically, found contribute regulation UC, some genes identified as potential regulators RBPs. Vene diagram significant overlap miRNA- RBP-targeted DEGs, suggesting may modulate through miRNA RBP targeting. Additionally, five key genes——CD38, NCALD, SMIM31, GPX7, SWAP70——were potentially playing crucial role This provides new insights into mechanisms technology, especially selection.

Language: Английский

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Identification of key genes and signaling pathway in the pathogenesis of Huntington's disease via bioinformatics and next generation sequencing data analysis

Egyptian Journal of Medical Human Genetics, Journal Year: 2025, Volume and Issue: 26(1)

Published: March 4, 2025

Abstract Background Huntington's disease (HD) could cause progressive motor deficits, psychiatric symptoms, and cognitive impairment. With the increasing use of pharmacotherapies theoretically target neurotransmitters, incidence HD is still not decreasing. However, molecular pathogenesis have been illuminate. It momentous to further examine HD. Methods The next generation sequencing dataset GSE105041 was downloaded from Gene Expression Omnibus (GEO) database. Using DESeq2 in R bioconductor package screen differentially expressed genes (DEGs) between samples normal control samples. ontology (GO) term REACTOME pathway enrichment were performed on DEGs. Meanwhile, using Integrated Interactions Database (IID) database Cytoscape software construct protein–protein interaction (PPI) network module analysis, identify hub with highest value node degree, betweenness, stress closeness scores. miRNA-hub gene regulatory TF-hub constructed analyzed. Receiver operating characteristic curves analysis for diagnostic genes. Results We identified 958 DEGs, consisting 479 up regulated DEGs down GO terms analyses by g:Profiler online results revealed that mainly enriched multicellular organismal process, developmental signaling GPCR MHC class II antigen presentation. Network Analyzer plugin PPI network, LRRK2, MTUS2, HOXA1, IL7R, ERBB3, EGFR, TEX101, WDR76, NEDD4L COMT selected as Hsa-mir-1292-5p, hsa-mir-4521, ESRRB SREBF1 are potential biomarkers predicted be associated Conclusion This study investigated key pathways interactions its complications, which might help reveal correlation complications. current investigation captured prediction, follow-up biological experiments enforced validation.

Language: Английский

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Inflammation and cancer: molecular mechanisms and clinical consequences

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: March 17, 2025

Inflammation, a hallmark of cancer, has been associated with tumor progression, transition into malignant phenotype and efficacy anticancer treatments in cancer. It affects all stages from the initiation carcinogenesis to metastasis. Chronic inflammation induces immunosup-pression, providing an environment conducive carcinogenesis, whereas acute antitumor immune response, leading suppression. Solid tumors have inflammatory microenvironment (TME) containing cancer cells, stromal soluble molecules, which plays key role progression therapy response. Both cells TME are highly plastic constantly change their phenotypic functional properties. Cancer-associated inflammation, majority consists innate important cell plasticity, development drug resistance. Today, combined used advanced technologies, such as single-cell RNA sequencing spatial molecular imaging analysis, pathways linking chronic largely elucidated. In this review article, we highlighted cellular mechanisms involved cancer-associated its effects on treatment We also comprehensively setting GI cancers.

Language: Английский

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Characterizing macrophage diversity in colorectal malignancies through single-cell genomics

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 21, 2025

Colorectal cancer (CRC) is one of the most common malignant tumors digestive tract, with increasing incidence and mortality rates, posing a significant burden on human health. Its progression relies various mechanisms, among which tumor microenvironment tumor-associated macrophages (TAMs) have garnered attention. Macrophage infiltration in solid associated poor prognosis linked to chemotherapy resistance many cancers. These biological behaviors depend heterogeneity macrophages. Tumor-promoting TAMs comprise subpopulations characterized by distinct markers unique transcriptional profiles, rendering them potential targets for anticancer therapies through either depletion or reprogramming from pro-tumoral an anti-tumoral state. Single-cell RNA sequencing technology has significantly enhanced our research resolution, breaking traditional simplistic definitions macrophage subtypes deepening understanding diversity within TAMs. However, unified elucidation nomenclature molecular characteristics this remains lacking. In review, we assess application conventional polarization colorectal malignancies explore several defined single-cell omics perspective recent years, categorizing based their functions.

Language: Английский

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