Background: Esophageal squamous cell carcinoma (ESCA) represents one of the most common aggressive malignancies worldwide. Insulin-like growth factor binding protein 1 (IGFBP1), a typical member of the IGF superfamily, is closely linked to adverse prognosis in numerous cancers. Up to now, little is known about its functional relevance to cell migration and tumor progression in ESCA. This work focuses on clarifying the relationship between IGFBP1 expression and the progression and migratory characteristics of ESCA. Methods: mRNA expression profiles from ESCA patients were obtained from the TCGA and GEO databases. Differential expression analysis was performed using R software(version 4.2.2), followed by an intersection of DEGs between datasets. The STRING database was applied to establish PPI networks. Cytoscape software(Version 3.7.2) was then used for visual presentation and hub gene identification. IGFBP1 expression was validated in ESCA tissues versus adjacent normal tissues. Prognostic correlation was assessed using GEPIA, while diagnostic and predictive values were evaluated through ROC analysis and Cox regression. Genetic alterations of IGFBP1 were analyzed via cBioPortal. Immune cell infiltration patterns were investigated using TIMER. Functional enrichment analyses (GO, KEGG) were performed on IGFBP1-associated DEGs. In the in vitro experiments, esophageal cancer cell lines (such as Eca109 and TE-1) and normal human esophageal epithelial cell lines (such as HEEC) were selected. The transcriptional level of IGFBP1 was examined using RT-qPCR, while Western blot analysis was conducted to validate its protein expression changes. Changes in the proliferative capacity of cancer cells after IGFBP1 silencing were detected by the CCK-8 assay, and cell migration capacity was determined via wound scratch assays to clarify the related biological effects. Results: Overall, 2870 DEGs were screened from the GEO database, 153 DEGs were screened from the TCGA database, and 34 genes were found to be common to both databases; 10 core genes were screened from the PPI network. IGFBP1 was abnormally expressed in esophageal cancer. Cox regression confirmed that IGFBP1 is an independent risk factor, and prognostic analysis indicated that IGFBP1 is closely associated with poor prognosis. Gene mutation analysis showed that amplification mutations are the most common type of IGFBP1 gene mutation, and genetic alterations in IGFBP1 in ESCA patients are significantly associated with overall survival (OS) (p = 0.0002568). GO analysis indicated that IGFBP1-related differentially expressed genes were enriched in organic anion transport, epidermal development, apical cell components, and metal ion transmembrane transporter activity. Pathway enrichment based on the KEGG database illustrated the main enrichment of target genes in neuroactive ligand-receptor interactions, calcium signaling and cAMP signaling pathways. Additionally, remarkable differences in immune cell infiltration were observed between IGFBP1 high-expression and low-expression subgroups through tumor immune profiling. IGFBP1 expression differed significantly between esophageal cancer cells and normal esophageal epithelial cells, as detected by RT-qPCR (p < 0.05). Moreover, knockdown of IGFBP1 markedly inhibited the proliferation (p < 0.05) and migration abilities (p < 0.05) of TE-1 and Eca109 cells. Conversely, IGFBP1 overexpression facilitated these cellular processes. Conclusions: As a key oncogenic driver for ESCA, IGFBP1 may participate in the oncogenesis of ESCA, possibly influencing clinical outcomes via IGF signaling and the tumor microenvironment. Its dual functions in tumor and immune systems suggest it might be a candidate for ESCA immunotherapy research.
Ubiquitin-Specific Protease 14 (USP14) is a proteasome-associated deubiquitinase historically viewed as a pro-tumorigenic driver of the ubiquitin-proteasome system (UPS) by stabilizing oncoproteins. Recent evidence expands this view, positioning USP14 as a central regulator that integrates tumor cell-intrinsic malignancy, tumor microenvironment (TME) remodeling, and resistance to multiple therapies. Importantly, USP14 exerts functions beyond canonical deubiquitination, including non-catalytic and scaffolding activities, and is subject to complex allosteric regulation. This review synthesizes emerging regulatory crosstalks that broaden the functional landscape of USP14 in cancer. We first outline the dynamic allosteric regulatory network of USP14 and its activation modes, emphasizing post-translational modifications (PTMs)-notably phosphorylation and lactylation-that modulate USP14 activity and connectivity beyond traditional links to cell cycle control and metabolism. We then consolidate the signaling frameworks through which USP14 contributes to resistance across therapeutic modalities, including targeted therapies, chemotherapy, radiotherapy, and immunotherapy, highlighting both shared and treatment-specific mechanisms. In parallel, we discuss context-dependent tumor-suppressive roles of USP14 and detail its non-catalytic scaffolding functions that reshape signaling outputs independent of enzymatic activity. Collectively, these classical and non-classical mechanisms depict USP14 as a systems-level coordinator of oncogenic signaling, adaptive stress responses, and microenvironmental interactions. By integrating catalytic and non-catalytic functions with PTM-driven allosteric regulation, we propose a unified regulatory model in which USP14 operates as a master node connecting malignancy, TME dynamics, and therapeutic resistance. This framework provides strategic guidance for developing next-generation allosteric inhibitors and combination strategies aimed at overcoming clinical drug resistance and exploiting context-specific vulnerabilities in USP14-regulated networks.
JMJD6 is an iron (Fe2+)- and α-ketoglutarate (2-OG)-dependent dioxygenase that exhibits multiple enzymatic activities. As a key regulator of epigenetic and post-transcriptional processes, JMJD6 is frequently overexpressed in various malignancies and is closely associated with poor patient prognosis. This review systematically examines the central role of JMJD6 in tumorigenesis and cancer progression. Specifically, JMJD6 directly promotes tumor cell proliferation, invasion, metastasis, and stemness maintenance through mechanisms such as p53 hydroxylation and activation of the β-catenin/c-Myc signaling pathway. Furthermore, JMJD6 actively influences the immunosuppressive tumor microenvironment that facilitates tumor immune evasion, for example, by promoting M2-type tumor-associated macrophage polarization through the STAT3/IL-10 axis. Consequently, JMJD6 emerges as a multifunctional enzyme connecting intrinsic oncogenic programs with extrinsic immunosuppressive microenvironments. Given its pivotal roles, JMJD6 has become a promising prognostic biomarker and therapeutic target. Targeting JMJD6, particularly in combination with immune checkpoint inhibitors, represents a promising but still experimental strategy that warrants further investigation. This review further summarizes recent advances in JMJD6-targeted small-molecule inhibitors and combination therapy strategies, while discussing current challenges and future directions for clinical translation.
Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), mediates histone H3 lysine 27 trimethylation (H3K27me3) and plays an important role in epigenetic transcriptional repression and oncogenesis. Although EZH2 mutations are well characterized in B-cell lymphomas, its role in cutaneous T-cell lymphomas, including mycosis fungoides (MF), remains incompletely understood. The aim of this study was to evaluate EZH2 expression in MF using immunohistochemistry and to investigate its association with clinicopathologic parameters and proliferative activity. A total of 46 patients with MF were retrospectively analyzed. The cohort comprised 41 patients with early-stage disease (IA-IB) and 5 patients with more advanced disease manifestations (plaque and tumor lesions, including stage IIB cases). Nuclear EZH2 expression was semiquantitatively scored, and the Ki-67 proliferation index was assessed. Associations between EZH2 expression and clinicopathologic variables were analyzed using nonparametric statistical tests, including the Kruskal-Wallis and Spearman correlation tests. EZH2 expression increased progressively with advancing disease stage and lesion morphology (P < 0.05). A significant positive correlation was observed between EZH2 expression and disease stage (r = 0.342; P = 0.02), and with the Ki-67 proliferation index (r = 0.575; P < 0.001). EZH2 expression showed no significant association with serum lactate dehydrogenase levels, β2-microglobulin levels, age, sex, or disease duration. The relatively small sample size, particularly the limited number of advanced-stage cases, and the retrospective design represent study limitations. These findings demonstrate that EZH2 expression parallels disease progression and proliferative activity in MF and suggest that EZH2 immunohistochemistry may serve as a useful adjunct marker reflecting biological disease activity in routine dermatopathologic evaluation.
Background: MEIS proteins are essential homeobox transcription factors that play critical roles in development and have been increasingly implicated in oncogenesis, including breast cancer. Methods: In this study, we identified and characterized novel small-molecule MEIS2 inhibitors through in silico docking targeting the active region of the human MEIS2 homeobox domain. Lead candidates MEISi-2E, MEISi-3, and MEISi-4 were identified with binding energies ranging from -3.0 to -3.90 kcal/mol. The inhibitory potential of these molecules was validated in vitro using a species-conserved MEIS-Luciferase Reporter construct containing the TGACAG targeted locus. Results: Our results demonstrate that MEISi-2E, MEISi-3, and MEISi-4 significantly suppress MEIS-driven luciferase activity and downregulate the expression of Meis1, Meis2, and downstream genes such as IL17RB, CDH1, EGR2, PAX6, and SERPINE1 while upregulating negative regulator TGIF1 and SOX3. In breast cancer cell lines, these inhibitors exhibited potent growth inhibition, with MEISi-3 showing an exceptional IC50 as low as 0.1 μM in SK-BR-3 cells. Mechanistic studies using flow cytometry revealed that these inhibitors induce dose-dependent apoptosis and necrosis. Importantly, the novel inhibitors showed minimal toxicity to healthy human dermal and MRC5 fibroblasts, suggesting a favorable safety profile. Conclusions: These findings establish these small molecules as promising therapeutic candidates for targeting MEIS2-dependent pathways in breast cancer.
Orogenital papillomatosis and squamous cell carcinoma is an emerging yet poorly understood complex disease of bottlenose dolphins (Tursiops truncatus and T. erebennus), both in the wild and under managed care. Previous studies have indicated a potential role of papillomaviruses and/or herpesviruses in the development of oncogenesis, although unbiased metagenomic approaches to examine the disease-associated virome in biopsied lesions have not been performed. Herein, we determined the viruses present in oral and genital lesions from both wild and managed care bottlenose dolphins from the southeastern United States through deep sequencing. The sampled dolphins were infected with two closely related but phylogenetically distinct lineages of delphinid gammaherpesvirus. Multiple different papillomaviruses were also detected, including a new species and several novel types of Tursiops papillomaviruses. Delphinid gammaherpesviruses were detected more often and at higher levels than papillomaviruses in both wild and managed care dolphins, although co-infections with both viruses were common. Additionally, we demonstrate that oral and genital swabs are an effective method for detecting viral infection in dolphins with or without lesions, providing a simple, non-invasive surveillance tool and an adjunct to surgical tissue biopsies. To build diagnostic tools for further study on viral diseases of bottlenose dolphins, we immortalized primary cells from oral frenulum biopsies via retroviral transduction of the simian virus 40 large T antigen gene, which was confirmed by immunoassays and chromosomal mapping. Elucidating the etiologic agent(s) and malignant transformation process of this important disease of dolphins may ultimately lead to the development of targeted therapeutics and/or preventative recommendations.
In vertebrates, SWI/SNF complexes, also known as BRG1/BRM-associated factor (BAF) complexes, come in three major subtypes, canonical BAF (cBAF or BAF), polybromo-associated BAF (PBAF) and non-canonical BAF (ncBAF), that are targeted to different types of chromosomal cis-regulatory gene expression control elements. Approximately 20% of malignancies exhibit mutations in genes coding for subunits of the SWI/SNF family of ATP-dependent chromatin remodelling complexes. SMARCD is an essential evolutionarily conserved subunit of these complexes in all eukaryotes. Whilst the integral role of SMARCD in targeting and stabilising the SWI/SNF complexes is conserved from yeast to plants to humans, the three human SMARCD paralogs display specific expression patterns underlying their functional divergence. Although, all three SMARCD paralogs exhibit context-dependent roles in cancer, acting as both tumour suppressors and oncogenes, it is SMARCD1 that appears to show the broadest oncogenic footprint across malignancies, driving proliferation, invasion and metastasis in diverse cancer types. Here we review the recent literature pertaining to the molecular and cellular roles of the mammalian SMARCD paralogs and discuss their roles in oncogenesis from those perspectives.
Breast cancer remains a leading cause of cancer-related mortality worldwide, with epigenetic mechanisms like N6 methyladenosine (m6A) modification playing a crucial role in tumorigenesis. The interaction between microRNAs and m6A regulators, such as the methyltransferase METTL14, is increasingly recognized as a key pathway in oncogenesis. This study investigated whether miR-30c-2-3p regulates METTL14 expression to influence global m6A levels and cell migration in breast epithelial (MCF12A) and breast cancer (MCF7) cell lines. Following transfection with miR-30c-2-3p mimics, successful overexpression was confirmed in both cell lines. Subsequent RT-qPCR and Western blotting analyses demonstrated that METTL14 mRNA and protein levels were significantly reduced at 24 and 48 h post-transfection (p < 0.05). Concurrently, global m6A RNA methylation levels decreased, with a more pronounced reduction observed in MCF12A cells (p < 0.001). Functionally, wound healing assays revealed that miR-30c-2-3p significantly inhibited migration, reducing wound closure by 30-44% in MCF7 cells and by 66-72% in MCF12A cells. These findings reveal a novel regulatory axis involving miR-30c-2-3p, METTL14, and m6A, suggesting that miR-30c-2-3p functions as a tumor suppressor and represents a promising biomarker and therapeutic target in breast cancer.
DNA/cell mass homeostasis is a pervasive feature of living organisms. As the cell grows in response to nutrient availability, it must duplicate each chromosome once and only once each division cycle. Across the eukaryote Tree of Life, cells differ in their sizes in a manner that depends directly on the amount of DNA they harbor, what has been termed the "nucleotypic effect": cell size expands or contracts as DNA content increases or decreases. In eukaryotes, any deviation from DNA/mass homeostasis results in the deregulation of the developmental program and the initiation of carcinogenesis and other genetic pathologies. In bacteria, deviation from, or perturbation of, DNA/mass homeostasis alters important physiological features such as the cell cycle timing of DNA replication initiation and the coordination of initiation with replication termination and cell division. In prokaryotes, the timing of initiation occurs at a relatively constant and growth-rate-invariant mass, termed the initiation mass (Mi), and depends strictly on DNA replication fork rates and membrane biogenesis. Complex "machines", frequently referred to as hyperstructures or factories, mediate the phase transitions that define the different periods of the bacterial cell cycle. The following will examine how DNA/mass homeostasis maintains a balance between DNA replication initiation and elongation in order to gate the phase transitions that organize the cell cycle in time and space.
Common cancers share germline susceptibility, yet the genetic architecture of a truly pan-cancer component of carcinogenesis remains incompletely resolved. We applied genomic structural equation modelling (gSEM) to genome-wide association studies (GWAS) summary statistics for 12 cancers (>600,000 European-ancestry cases) to separate a latent pan-cancer genetic factor from cancer-specific components, and then performed a multivariate GWAS of that factor. We conducted comprehensive downstream genetic, predictive, and functional analyses to characterise the resulting pan-cancer factor. We identified 133 LD-independent loci associated with the pan-cancer factor, including eight loci not previously associated with any cancer phenotype. Pan-cancer genetic risk was concentrated in evolutionarily conserved regulatory DNA, with enrichment in promoter and enhancer annotations and tissue-relevant signals in mammary and uterine contexts. A pan-cancer polygenic risk score (PRS) derived from the latent-factor GWAS improved prediction of overall cancer in UK Biobank (Royston-Sauerbrei R2 = 2.97%), showed significant predictive value for most assessed cancers (R2 up to 8.66%), and retained predictive signal in an independent East Asian validation dataset (Nagelkerke R2 = 0.56%), outperforming a previous meta-analysis-based cross-cancer PRS and all site-specific PRSs. Gene and pathway prioritisation identified 132 putative risk genes across 106 loci, including 21 genes with little or no prior cancer annotation, and implicated canonical genome maintenance and cell cycle programmes alongside less emphasised processes involving organelle organisation, vesicle trafficking, and protein post-translational modification. Finally, proteome-wide Mendelian randomisation identified 23 blood proteins with putative causal effects on pan-cancer risk, including six druggable targets. Together, these results delineate a gSEM-derived pan-cancer genetic architecture, provide a cross-site PRS for overall cancer susceptibility, and nominate genes and circulating proteins for functional follow-up and prevention-oriented target discovery. Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Natural Science Foundation of China, and National Key Research and Development Program of China.
Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with chronic inflammation playing a central role in its pathogenesis. While established risk factors such as Helicobacter pylori (Hp), diet, and lifestyle are well recognized, growing epidemiological evidence links airborne particulate matter (PM) exposure with increased GC incidence and mortality. However, the biological mechanisms underlying this association remain poorly understood. This review integrates epidemiological evidence associating elevated PM exposure with GC risk and summarizes current mechanistic knowledge regarding PM gastric translocation and retention. The influence of PM size, chemical composition, and surface reactivity on biological activity is also discussed, highlighting the stomach as a plausible yet understudied target organ. Additionally, we compiled evidence from studies published between 2010 and 2026 demonstrating the ability of PM to induce inflammatory responses through activation of NF-κB, MAPK, JAK/STAT, and COX-2 signaling pathways across diverse biological systems. Although PM-induced inflammation has been extensively characterized in respiratory and other tissues, its contribution to gastric carcinogenesis remains largely unexplored. We propose that PM exposure may exacerbate Hp-driven inflammation, promoting a persistent pro-inflammatory microenvironment conducive to tumor initiation and progression. Collectively, these findings position PM as a biologically plausible and potentially modifiable risk factor for GC.
The high clinical recurrence rate of colorectal cancer (CRC) is driven by the survival of residual tumor cells that evade therapy-induced death by entering a dormant state. While dormancy is a recognized mechanism of treatment resistance, the molecular drivers governing this "quiescent reservoir" and its associated vulnerabilities remain poorly characterized, limiting the development of strategies to eradicate these dormant seeds. We developed a COAD-specific Dormancy Score (CADS) derived from NMF analysis of ~ 69,000 single cells to quantify and identify a dormant subpopulation at single-cell resolution. Mechanistically, the IFN-β/cDC1 axis and its downstream MEK/ERK dependency were validated using a GFP-p27K- dormancy reporter system, spatial transcriptomics, and CRISPR/Cas9-mediated Ifnar1 knockdown. Finally, the synergistic efficacy of anti-PD-1 combined with MEK inhibition (Trametinib) was evaluated in orthotopic CRC mouse models. The CADS effectively identified a distinct dormant subpopulation in CRC characterized by profound G0/G1 arrest, enhanced stemness, and multi-drug resistance. We uncovered a novel evasion mechanism mediated by the hijacking of IFN-β signaling. Conventionally recognized for its anti-proliferative roles, IFN-β signaling is exploited by surviving tumor cells to enter a deep quiescent state. This phenotype acts as a biological reservoir that fuels intratumoral heterogeneity and underpins the relapse of colorectal tumors by conferring resistance to conventional cytotoxic regimens. Effective anti-PD-1 therapy paradoxically enriches this dormant population via an enhanced IFN-β-conventional type 1 dendritic cell (cDC1) axis. Mechanistically, IFN-β-induced dormancy depends on MEK/ERK pathway activity, which sustains survival while suppressing apoptosis. This creates a synthetic lethal vulnerability: MEK inhibition (e.g., Trametinib) synergizes with IFN-β to re-sensitize dormant cells to apoptosis. Consequently, combining Trametinib with anti-PD-1 therapy overcomes this evasion mechanism, eliminates the dormant subpopulation, remodels the immune microenvironment, and shows strong synergistic efficacy in preclinical models. Our work redefines an immune-cell death paradox, revealing how tumors exploit IFN-β to evade therapy. We propose CADS as a translational biomarker for identifying tumors reliant on this pathway and validate a mechanism-based combination therapy that selectively targets dormancy-associated death resistance, offering a promising strategy to improve CRC outcomes.
Cervical cancer remains a leading cause of cancer-related mortality among women worldwide, with mortality disproportionately concentrated in low-and middle-income countries (LMICs), where screening infrastructure is limited. Although persistent high-risk human papillomavirus (hrHPV) infection drives nearly all cervical cancers through a prolonged preinvasive window, making the disease both preventable and detectable, current screening modalities face biological and operational limitations that constrain their global impact. Cytology-based methods suffer from moderate sensitivity and subjective interpretations. HPV DNA testing is highly sensitive, it lacks specificity for transforming infections and shifts the diagnostic burden toward triage and colposcopy. Meanwhile, visual inspection methods are accessible, they offer limited reproducibility. In this review, we adopt a target-centric diagnostic framework that organizes cervical cancer screening not by detection platform but by the biological class of the marker being interrogated. We first examined the molecular pathogenesis of cervical carcinogenesis, including HPV genotype-specific biology, viral integration dynamics, oncogene-driven transformation, and epigenetic consolidation, to establish the biological rationale for each biomarker category. We then systematically evaluated conventional screening modalities and their limitations before reviewing emerging diagnostic technologies across four target domains: HPV-derived markers (DNA, mRNA, capsid proteins), host cell-cycle regulators (p16INK4a, Ki-67), non-protein biomarkers (biothiols, volatile metabolites), and marker-free platforms (Raman/FT-IR spectroscopy, AI-assisted cytopathology). Particular emphasis is placed on point-of-care (POC) deployability, noninvasive sampling strategies, and the integration of multilayered risk stratification into scalable screening pathways. By mapping diagnostic innovation onto the biological continuum of cervical carcinogenesis, this review provides a conceptual foundation for developing next-generation screening approaches that align molecular precision with global accessibility, thereby supporting progress toward the World Health Organization goal of cervical cancer elimination.
Herpes simplex virus type 1 (HSV-1) remains a significant pathogen, particularly in immunocompromised patients. The emergence of drug-resistant strains necessitates alternative therapeutic agents. Lentinula edodes (LE), Hypsizygus marmoreus, and Pleurotus eryngii are edible mushrooms with recognized medicinal properties. However, their effects on drug-resistant HSV-1 remain unclear. This study characterized metabolites from high-temperature/high-pressure (121 °C) water extracts of fresh and dried fruiting bodies and evaluated anti-HSV-1 activities using in vitro and in silico approaches. Metabolic profiles were analyzed by electrospray ionization-quadrupole time-of-flight mass spectrometry. Antiviral activity against HSV-1 KOS (wild-type) and HSV-1 dxpiii (drug-resistant) strains was assessed by plaque assays and qPCR. Molecular docking and network pharmacology were performed on candidate compounds. LE extract from dried mushroom tended to show the highest levels of selected major bioactive constituents, along with greater antioxidant activities. All extracts significantly inhibited viral infection and gene expression in both strains. LE extract from dried mushroom modulated the expression of NFKB1 and IL6. Molecular docking analysis revealed that eritanidine showed a predicted binding affinity to HSV-1 DNA polymerase (-7.95 kcal/mol). Additionally, eritanidine, 5'-methylthioadenosine, and 3-indoleacrylic acid were predicted to interact with TNF and MAPK1. Several compounds also demonstrated favorable drug-likeness properties. Overall, these mushroom extracts are promising natural sources of antiviral agents against HSV-1, including drug-resistant variants.
Helicobacter pylori (H. pylori) infection is a major risk factor for gastric cancer (GC), yet the key genes mediating this carcinogenesis remain unclear. This study aimed to identify H. pylori-related genes in GC and elucidate their molecular functions. Transcriptomic data from TCGA and GEO databases were analyzed using weighted gene co-expression network analysis (WGCNA), LASSO regression, and multivariate Cox analysis to construct a prognostic model. The immune landscape was also assessed. Validation involved RT-qPCR and immunohistochemistry (IHC). An in vitro H. pylori co-culture system was used to assess time-dependent changes in gene and protein expression via RT-qPCR, IHC, and Western blotting. A four-gene risk model (PDCD1, KYNU, CYTL1, and FZD2) was identified, demonstrating strong predictive capacity for overall survival as an independent prognostic factor. High-risk patients exhibited reduced immune cell infiltration. CellMiner analysis identified potential therapeutic agents targeting these genes. Among them, KYNU showed significant upregulation in GC tissues. Notably, in the co-culture system, KYNU expression markedly increased at both mRNA and protein levels following H. pylori infection in a time-dependent manner. The H. pylori-associated risk model represents a novel independent prognostic indicator for GC. Particularly, KYNU emerged as a pivotal gene in H. pylori-mediated GC, offering insights into disease progression and serving as a promising therapeutic target.
This systematic review with meta-analysis aims to analyse the existing literature on clinicopathological features of sporadic gastric hyperplastic polyps (GHP), with special emphasis on risk factors associated with neoplastic transformation, as well as available immunohistochemical and molecular data relevant to GHP carcinogenesis. We searched two electronic databases and included studies reporting the presence of dysplasia and adenocarcinoma arising in GHP. Meta-analysis of odds ratios (ORs) was performed using random-effects models. We included 58 studies, 11 of which were included in quantitative synthesis. The overall rate of neoplastic transformation in GHP was 6.0% and progression to adenocarcinoma was observed in 1.5%. Statistically significant risk factors for neoplastic transformation were age ≥65 years (OR 2.60; 95% confidence interval [CI] [1.88-3.59]), size ≥20 mm (OR 4.63; 95% CI [1.82; 11.77]) with increasing size thresholds, as well as intestinal metaplasia (OR 3.65; 95% CI [1.68; 7.97]). Although the evidence is limited, the available data suggest that GHP located in the cardia or arising in a dysplastic background gastric mucosa may represent higher-risk subsets. Immunohistochemical subtyping of dysplasia showed a progressive shift from a predominantly gastric phenotype in non-neoplastic GHP to a hybrid (gastric-intestinal) phenotype in dysplasia and adenocarcinoma. TP53 alterations and chromosomal instability were the most frequently reported molecular events. GHP present a significant neoplastic potential, particularly in the presence of additional clinicopathological risk factors. Lesion size, patient age and - above all - the status of the surrounding gastric mucosa should guide endoscopic management, pathological interpretation and surveillance strategies.
Assessment of the carcinogenic potential of chemicals is considered an important element of human health risk assessment. However, the approaches currently used for different regulatory sectors have some shortcomings. To overcome these, an alternative testing strategy, like an IATA (Integrated Approach to Testing and Assessment), for the detection of non-genotoxic carcinogens (NGTXCs) is in demand. Such an IATA should be mechanism-based and, wherever possible, consist of New Approach Methodologies (NAMs) to avoid testing in experimental animals. To explore which type of NAMs (in silico and in vitro) should be included in the first tier of an IATA for NGTXCs we performed a case study, in line with various international initiatives focusing on this need. The case study comprised a diverse set of 29 chemicals that together cover different modes of action relevant for non-genotoxic carcinogenesis. Different NAMs, including in silico tools (e.g., QSARS, ADME predictions) and high-throughput in vitro assays such as ToxCast and CALUX, were explored. The findings from the case study reveal the complementarity of the NAMs studied as well as the need for additional NAMs to be included, to ensure a broader coverage of MOAs relevant for carcinogenicity. As such, the case study nicely contributes to a more defined composition of a first tier for an IATA for NGTXC. Next-generation risk assessment (NGRA) aims to make chemical risk assessment more human‑relevant and mechanism-based using alternatives to animal testing. In this study, we explored which new approach methods (NAMs), such as computer models (in silico) and cell‑based tests (in vitro), can be used as a first screening step for non‑genotoxic carcinogenesis. We applied a set of NAMs to chemicals that are known to be (non-)carcinogenic. The results show that these methods provide complementary information and that combining them gives a more complete picture than using any single method alone. At the same time, some important cancer‑related mechanisms are still not well covered, underlining the need for additional NAMs and better datasets. Our work supports the goals of NGRA and the 3Rs principle by promoting alternatives to animal testing and helping to design more informative and efficient early‑tier testing approaches for screening potential carcinogenic mechanisms.
Skin cancer presents a significant global health burden with rising incidence. The side effects of current therapies and the emergence of drug resistance necessitate the exploration of alternative and complementary strategies. Natural products, with their long history of use in treating skin disorders, have emerged as a promising source of novel therapeutic agents. This review comprehensively elucidates the potential efficacy of natural bioactive compounds in both preventing and treating skin cancer. We summarize the molecular mechanisms through which key natural bioactive compounds exert their anti-skin cancer effects, including induction of apoptosis, inhibition of proliferation and metastasis, anti-inflammatory and antioxidant activities, DNA damage repair, and photoprotection. Furthermore, we discuss the biological barriers relevant to skin cancer therapy using natural bioactive compounds and link them to corresponding delivery strategies, while identifying key translational challenges. In conclusion, natural bioactive compounds offer a multi-targeted and synergistic approach against skin carcinogenesis, holding substantial promise as sources of adjuvant therapies and chemopreventive agents to improve patient outcomes.
This study aimed to explore the core active ingredients and potential molecular mechanisms of Erjing Pills, a prescription in the classic work of Traditional Chinese Medicine, "Shengji Zonglu," in the treatment of leukotrichia by utilizing network pharmacology and biomolecular docking techniques. The chemical components and potential targets of Chinese herbal medicines were analyzed through databases such as the Traditional Chinese Medicine Systems Pharmacology Database. The targets related to leukotrichia were collected using GeneCards. The intersection targets were obtained using RStudio. The protein-protein interaction (PPI) network map and the "drug-component-target-disease" visualization network were generated using Cytoscape and STRING to screen the core components and key targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were carried out using the Database for Annotation, Visualization and Integrated Discovery and RStudio. Finally, molecular docking verification was performed by AutoDock and PyMOL (Schrödinger LLC). The key active ingredients of Erjing Pills in the treatment of leukotrichia are β-sitosterol, quercetin, baicalein, and stigmasterol. The top 5 PPI core target proteins, in order, are AKT serine/threonine kinase 1, interleukin 6, tumor protein p53, cysteine-aspartic acid protease 3, and interleukin 1 beta. The Gene Ontology enrichment analysis suggests that the biological processes mainly include responses to exogenous stimuli, membrane rafts, and DNA-binding transcription factor binding. The Kyoto Encyclopedia of Genes and Genomes pathways involve signal pathways such as lipid and atherosclerosis, hepatitis B, Kaposi sarcoma virus infection, chemical carcinogenesis, and human cytomegalovirus infection. The molecular docking results indicate that most of the main active ingredients in Erjing Pills have relatively stable binding activities with the key targets, such as AKT serine/threonine kinase 1, interleukin 6, tumor protein p53, cysteine-aspartic acid protease 3, and interleukin 1 beta, in the PPI network. The active ingredients of Erjing Pills may interfere with the pathological process of leukotrichia by regulating key targets and signal pathways. This study provides a theoretical basis for the clinical application of Erjing Pills and indicates the direction for subsequent experimental research.
Oral squamous cell carcinoma (OSCC) frequently develops within chronically injured oral mucosa and may be preceded by clinically recognizable oral potentially malignant disorders (OPMDs), which provide an important window for cancer interception. This review examines how etiological exposures, persistent inflammation, and lesion-specific epithelial-stromal-immune interactions cooperate during the transition from mucosal injury to dysplasia, carcinoma in situ, and invasive OSCC. Major carcinogenic exposures, including tobacco, alcohol, and areca nut, are considered together with context-dependent contributors such as microbial dysbiosis, viral infection, and immune-mediated epithelial injury. At the molecular level, inflammation-driven oral carcinogenesis involves cytokine and chemokine amplification, oxidative and nitrosative stress, NF-κB and STAT3 activation, the COX-2/PGE2 axis, genomic instability, field cancerization, epithelial-stromal crosstalk, angiogenesis, immune dysregulation, and epigenetic and non-coding RNA-mediated reprogramming. Emerging tools such as molecular risk assessment, liquid biopsy, optical imaging, spatially resolved profiling, and artificial intelligence-assisted models may improve identification of high-risk lesions, although most biomarkers require further prospective validation. Prevention should therefore integrate exposure control, biopsy-based diagnosis, local treatment when indicated, long-term surveillance, and trial-based precision strategies according to lesion risk, intervention window, and safety profile. This review supports a shift from lesion-centered management toward risk-adapted precision prevention in inflammation-driven oral carcinogenesis.