Search Results (4,817)

Background: Lung cancer ranks among the most common and deadly malignant tumors worldwide. Drug resistance is a critical factor hindering the effect of chemotherapy for lung cancer. Exosomes, as intercellular signaling molecule carriers, play an important role in carcinogenesis, metastasis and drug resistance. Our study was aimed at exploring the impact of exosomes derived from docetaxel (DTX)-resistant lung cancer cells on regulating biological behaviors of DTX-sensitive cells, further investigating the molecular mechanisms regarding exosome-mediated intercellular communication. Methods: We extracted and identified the exosomes derived from A549, A549/DTX, H1299 and H1299/DTX cells, and then analyzed the expression of exosomal miR-373-3p between DTX-sensitive and DTX-resistant cells. Cell proliferation and apoptosis experiments were verified using a CCK-8 assay, a colony formation assay, a TUNEL assay and flow cytometry. The molecular interaction between miR-373-3p and PDCD4 was evaluated using a dual-luciferase reporter assay. The function of miR-373-3p was further assessed using an in vivo mouse xenograft model. Results: We found that the exosomal miR-373-3p level from DTX-resistant A549/DTX or H1299/DTX cells significantly exceeded that from DTX-sensitive A549 or H1299 cells. In addition, both exosomes derived from DTX-resistant lung cancer cells and miR-373-3p mimics could promote the proliferation of DTX-sensitive cells and inhibit their apoptosis. Moreover, we identified PDCD4 as a key target gene of miR-373-3p, which could induce the malignant behaviors of DTX-sensitive cells by reducing PDCD4 expression. Conclusions: Our results demonstrated that DTX-resistant lung cancer cells could transfer miR-373-3p to DTX-sensitive cells through exosomes, where miR-373-3p could exert its carcinogenic effect via targeting PDCD4. Full article

Thyroid cancer is the most common malignancy of the endocrine system and represents a biologically heterogeneous disease driven by the interplay between endocrine regulation, oncogenic signaling pathways, and tumor microenvironment dynamics. Although most follicular cell-derived thyroid cancers follow an indolent clinical course, a subset progresses toward aggressive, therapy-refractory phenotypes, underscoring the need for refined molecular understanding and improved biomarkers. This review comprehensively examines the molecular determinants of thyroid cancer progression, with particular emphasis on Thyroid Hormone (TH) signaling, the Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)/AKT pathways, and the emerging role of microRNAs (miRNAs). We discuss how oncogenic alterations, most notably the ^V600EBRAF mutation, act as central drivers of tumor initiation and aggressiveness by sustaining MAPK/ERK signaling, promoting dedifferentiation, metabolic reprogramming, immune evasion, and resistance to targeted therapies. The cooperative role of PI3K/AKT signaling in reinforcing survival, invasion, and treatment resistance is highlighted, emphasizing the network-level integration of oncogenic pathways rather than linear dependency on single drivers. In parallel, thyroid hormones exert context-dependent effects on tumor biology through both genomic actions mediated by nuclear thyroid hormone receptors and non-genomic mechanisms initiated at the integrin αvβ3 receptor, linking endocrine status to cancer progression and therapeutic response. Finally, we review the expanding evidence supporting miRNAs as critical regulators of thyroid carcinogenesis and as promising diagnostic, prognostic, and predictive biomarkers. The clinical validation of miRNA-based panels and circulating miRNAs offers new opportunities to improve preoperative risk stratification, reduce overtreatment, and guide personalized therapeutic strategies. Collectively, these insights support a multidimensional framework for understanding thyroid cancer progression and highlight future directions for precision oncology. Full article

Background: Metabolic dysregulation is increasingly recognized as a contributor to carcinogenesis; however, the role of circulating lipid traits in ovarian cancer remains unclear. Methods: A systematic review and meta-analysis were conducted following PRISMA 2020 guidelines. PubMed, Web of Science, Scopus, and Embase were searched from inception to March 2026. Observational studies evaluating triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) in relation to ovarian cancer risk were included. Random-effects models were used to pool relative risks (RRs). Robustness was assessed via sensitivity analyses, influence diagnostics, and multiverse analysis. Mendelian randomization (MR) evidence was integrated for causal inference. Results: Six observational studies were included in the meta-analysis. Elevated triglyceride levels were associated with increased ovarian cancer risk, while HDL-C showed a modest inverse association. LDL-C and total cholesterol were not significantly associated with risk. Sensitivity analyses excluding early follow-up strengthened the triglyceride association. MR analyses supported a potential causal role for triglycerides but not for HDL-C. Conclusions: Circulating triglycerides may represent a metabolically relevant risk factor for ovarian cancer. Further large-scale prospective and mechanistic studies are warranted. Full article

Background: Colorectal intraepithelial neoplasia (CR-EN) is a precursor lesion of colitis-associated colorectal cancer (CAC). This study investigated the interventional effects and molecular mechanisms of Rhapontici Radix extract on CR-EN. Methods: An azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mouse model of colonic intraepithelial neoplasia, bioinformatics analysis, organoid models, and HCT116 cell experiments were employed, coupled with histopathological examination, inflammatory cytokine detection, Western blot, immunofluorescence, and HPLC-MS/MS. Results: The results showed that the YAP/AKT-PI3K signaling pathway is aberrantly activated in CRC. Rhapontici Radix extract ameliorated colonic pathology, suppressed inflammatory responses, and remodeled gut microbiota composition in model mice. The extract selectively inhibited the proliferation of CR-EN organoids by downregulating Ki67 and β-catenin while upregulating p53, and suppressed the proliferation, colony formation, and migration of HCT116 cells. Mechanistically, the extract modulated the YAP/PI3K/AKT pathway by upregulating phosphorylated YAP (p-YAP) and downregulating phosphorylated AKT (p-AKT), phosphorylated PI3K (p-PI3K), and their downstream targets p-SRC and c-MYC. Conclusions: This study suggests that Rhapontici Radix extract intervenes in inflammation-associated carcinogenesis through a multi-pathway, multi-target strategy, offering potential therapeutic targets for CAC prevention and treatment. Full article

Colorectal cancer (CRC) is a multifactorial disease influenced by genetic and environmental factors. The endothelial nitric oxide synthase (eNOS) gene, involved in nitric oxide (NO) production, is associated with carcinogenesis. This study aimed to evaluate the association between eNOS −786T>C and G894T polymorphisms and CRC susceptibility in an Algerian population. Genotype and allele frequencies were analyzed, and associations were assessed using odds ratios (ORs) and 95% confidence intervals (CIs). For −786T>C polymorphism, the CC genotype was significantly more frequent in patients than in controls (37.33% vs. 21.67%) and was associated with increased risk of CRC (OR = 2.15, 95% CI: 1.21–3.88, p = 0.004), whereas the TT genotype showed a protective effect (OR = 0.41, 95% CI: 0.20–0.81, p = 0.005). Regarding the G894T polymorphism, the TT genotype was significantly associated with increased susceptibility to CRC (44.67% vs. 8.33%; OR = 8.88, 95% CI: 4.19–15.40, p < 0.001), while the GG genotype was protective (OR = 0.18, 95% CI: 0.10–0.32, p < 0.001). Allelic analysis confirmed that the C and T alleles were risk factors. Furthermore, eNOS polymorphisms were significantly associated with tumor location. In conclusion, the eNOS −786T>C and G894T polymorphisms are significantly associated with CRC susceptibility in the Algerian population and could serve as potential genetic biomarkers. Full article

Background and Objectives: Gastric cancer remains a leading cause of cancer-related mortality worldwide and develops through complex interactions between environmental factors, microbial dysbiosis, and host molecular pathways. Although Helicobacter pylori infection is a well-established risk factor, emerging evidence suggests that broader alterations in the gastric microbiome may also contribute to carcinogenesis. However, the associations between gastric cancer-associated microbial taxa and host gene expression profiles remain insufficiently characterized. This study aimed to identify host gene signatures associated with gastric cancer-related microbial taxa through a descriptive analysis integrating microbiome-derived taxa with transcriptome data. Materials and Methods: Microbial taxa associated with gastric cancer were systematically retrieved from the Disbiome database. Taxon set enrichment analysis (TSEA) was performed using the MicrobiomeAnalyst platform to identify host genes associated with gastric cancer-associated taxa. Importantly, TSEA relies on healthy reference data from the Human Microbiome Project and does not establish gastric cancer-specific interactions or causal relationships. Gene expression levels were subsequently evaluated using The Cancer Genome Atlas (TCGA) PanCancer stomach adenocarcinoma (STAD) dataset by comparing tumor and matched normal gastric tissues. Gene interaction network and transcription factor (TF) enrichment analyses were conducted to explore predicted regulatory relationships. Results: Among 64 microbial taxa associated with gastric cancer, 43 were reported as elevated. After removing overlapping taxa across studies, 37 elevated and 21 reduced taxa were retained for analysis. TSEA identified 11 host genes associated with gastric cancer-related microbial taxa. Transcriptomic analysis demonstrated significant downregulation of DPP6 and DLG2, while KDM4D, USP34, and VDR were significantly upregulated in gastric cancer tissues compared with normal controls. Network and TF enrichment analyses revealed predicted co-expression and co-localization patterns among these genes, suggesting their potential involvement in immune-related processes, epigenetic regulation, and cellular organization. Conclusions: This descriptive study identifies distinct host gene expression signatures associated with gastric cancer-associated microbial dysbiosis. This study is purely associative and hypothesis-generating; no causal or mechanistic inferences are made. TSEA used healthy reference data and therefore does not reflect gastric cancer-specific host–microbe interactions. The findings provide a basis for future hypothesis-driven research but require validation in independent cohorts. Full article

Background/Objectives: The clinical management of bladder cancer is severely impeded by high recurrence rates and the rapid emergence of chemoresistance, necessitating the discovery of novel therapeutic agents with distinct mechanisms of action. Dehydrodiisoeugenol (DHE), a bioactive neolignan, exhibits potent anti-tumor efficacy, yet its direct molecular targets and mode of action remain elusive. Methods: To deconvolute the mechanism of DHE, we integrated a phenotypic screening approach using 2D cell lines and 3D patient-derived organoids with a chemoproteomics-based activity-based protein profiling (ABPP) strategy. We synthesized a functionalized photoaffinity probe to capture the specific interactome of DHE under physiological conditions and validated targets via cellular thermal shift assays (CETSA), quantitative mass spectrometry, and 100 ns molecular dynamics (MD) simulations. Results: DHE exhibited potent dose-dependent cytotoxicity in bladder cancer cells, with IC50 values of 39.23μM in T24 and 34.58μM in 5637 cells. In 3D patient-derived organoids, DHE significantly reduced viability (p < 0.0001). Using a dual-filtering ABPP strategy, we identified 65 high-confidence candidate targets, prioritizing PTPN1 (PTP1B) as the primary functional interactor. Comparative molecular docking and 100 ns MD analyses showed that multiple stereoisomers of DHE could adopt plausible PTPN1-binding modes. Mechanistically, organoid proteomics indicated that DHE engagement with PTPN1 disrupts ER membrane homeostasis, thereby modulating the PI3K-Akt signaling axes. Conclusions: These findings establish PTPN1 as a critical druggable vulnerability in bladder cancer and define the molecular basis for the therapeutic potential of DHE. This study highlights the power of combining chemoproteomics with physiological 3D models to accelerate the translation of natural products into precision cancer therapies. Full article

Cholangiocarcinoma (CCA) is an aggressive malignancy with a poor prognosis that is strongly associated with chronic Clonorchis sinensis (C. sinensis, Cs) infection; however, its underlying molecular mechanisms remain elusive. Recent studies suggest that C. sinensis-derived extracellular vesicles (CsEVs) play a crucial role in host–parasite interactions and in shaping the tumor microenvironment during infection. Acting as key delivery vehicles, these CsEVs can transfer specific functional molecules, such as microRNAs (miRNAs), to host cholangiocytes, thereby modulating cellular behaviors—a process that may represent a significant pathway in parasite-induced carcinogenesis. Despite this, the specific miRNAs shuttled by CsEVs and their concrete functions and mechanisms in driving CCA proliferation and metastasis remain largely unexplored. To this end, we investigated Csi-miR-125a, a miRNA abundantly expressed in CsEVs, aiming to systematically elucidate its dual regulatory functions in CCA progression. Our findings offer novel mechanistic insights into host–parasite crosstalk, further the understanding of CCA pathogenesis, and point to potential therapeutic avenues. Using gain-and loss-of-function approaches in RBE and HuCCT1 cell lines, we demonstrated that Csi-miR-125a promotes cell proliferation by accelerating cell-cycle progression and suppressing apoptosis through direct targeting of BAK1. Concurrently, Csi-miR-125a enhances the migratory and invasive capacities of CCA cells via activation of the ERK signaling pathway. In a BALB/c nude mouse lung metastasis model, CsEVs depleted of Csi-miR-125a significantly inhibited pulmonary metastasis. Collectively, This study found that Csi-miR-125a derived from C. sinensis can regulate apoptosis and cell cycle progression by targeting BAK1, thereby promoting the proliferation of cholangiocarcinoma cells; meanwhile, it enhances cell migration and invasion by activating the ERK signaling pathway. These results suggest that Csi-miR-125a participates in and promotes the malignant progression of CCA. However, given its high homology with human endogenous miR-125a, its function may partially overlap with host endogenous miRNAs, rather than representing a completely independent carcinogenic effect. These findings provide mechanistic insights into host–parasite interactions during C. sinensis infection and lay a theoretical foundation for subsequent targeted intervention studies. Full article

Background/Objectives: Oral squamous cell carcinoma (OSCC) accounts for over 90% of oral malignancies and remains associated with substantial global morbidity and mortality. Although tobacco and alcohol are established risk factors, they do not fully explain OSCC incidence, highlighting the need to explore additional contributors such as chronic inflammatory conditions. Periodontal disease, characterized by persistent inflammation and microbial dysbiosis, has emerged as a plausible factor in oral carcinogenesis and tumor progression. To systematically evaluate the association between periodontal disease and the risk of developing OSCC, and to assess the prognostic impact of periodontal disease–related factors, particularly intratumoral Porphyromonas gingivalis, on survival outcomes in patients with OSCC. Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines and prospectively registered in PROSPERO (CRD420261296479). Comprehensive searches were performed in PubMed, EMBASE, Web of Science, Scopus, the Cochrane Library, ClinicalTrials.gov, and World Health Organization regional databases. Case–control studies evaluating OSCC risk and cohort studies assessing survival outcomes were included. Random-effects meta-analyses using inverse-variance models were applied. Heterogeneity was assessed using the I² statistic, and robustness was evaluated through Hartung–Knapp adjustment, leave-one-out sensitivity analyses, and Trial Sequential Analysis. Results: Five case–control studies were included in the etiological analysis. Periodontal disease was significantly associated with an increased risk of OSCC (pooled OR = 3.17; 95% CI: 1.94–5.21), with moderate heterogeneity (I² = 58.7%). Two cohort studies were included in the prognostic analysis. High intratumoral expression of P. gingivalis was significantly associated with poorer overall survival (pooled HR = 2.15; 95% CI: 1.33–3.47), with no detected heterogeneity (I² = 0%). Conclusions: Periodontal disease is strongly associated with an increased risk of OSCC, and intratumoral P. gingivalis appears to be an adverse prognostic marker. These findings underscore the relevance of periodontal inflammation and microbial factors across the OSCC continuum, from carcinogenesis to clinical outcomes, and support their consideration as potential targets for risk stratification and prevention strategies. Full article

Macrophages are highly plastic cells of the tumor microenvironment, and although classically activated M1 macrophages are generally regarded as anti-tumor effectors, their prolonged cytotoxic activity may also promote tumor adaptation. In this study, we investigated whether sustained exposure of prostate cancer cells to cytotoxic M1-like macrophages results in the selection of tumor cell populations with enhanced malignant properties. Macrophage-resistant derivatives of the human prostate cancer cell lines PC3 and DU145 were generated by repeated co-culture with cytotoxic THP-1-derived macrophages and characterized in vitro and in vivo. Macrophage-selected tumor cells showed increased proliferative activity and enhanced clonogenic survival. In vivo, these cells formed larger xenograft tumors with more aggressive histopathological features. At the same time, their migratory activity was not significantly increased, although they displayed partial epithelial–mesenchymal transition-like changes, including increased vimentin expression without a marked loss of epithelial markers. Transcriptomic profiling revealed coordinated inflammatory and adaptive reprogramming, characterized by the enrichment of cytokine- and immune-response pathways together with the suppression of metabolic and differentiation-associated programs. These changes were accompanied by the selective activation of p38 MAPK signaling, while sensitivity to paclitaxel remained unchanged. Taken together, the results indicate that macrophage cytotoxicity may act as a selective pressure promoting the emergence of inflammation-adapted tumor cell variants with increased malignant potential, supporting re-evaluation of the role of M1-like macrophages in tumor progression. Full article

Trained immunity is a concept that is currently in development and refers to the long-term functional reprogramming of innate immune cells in response to microbial or inflammatory stimuli. This process serves a dual purpose in the gastrointestinal tract, contributing to chronic inflammatory conditions like inflammatory bowel disease and maintaining host defense. The production of pro-inflammatory mediators is augmented by epigenetic and metabolic changes that are induced by the persistent activation of innate immune cells, which is triggered by microbial components and damage-associated signals. Although this increased responsiveness may initially be protective, sustained activation leads to tissue damage, epithelial barrier dysfunction, and chronic inflammation. These mechanisms are significant contributors to colorectal carcinogenesis, particularly in colitis-associated cancer. Through the activation of oncogenic signaling pathways, the establishment of a pro-tumorigenic microenvironment, and an increase in oxidative stress, trained immunity also influences tumor development. Additionally, the systemic reprogramming of hematopoietic progenitor cells has the potential to exacerbate inflammation and facilitate the progression of tumors. The identification of epigenetic and metabolic biomarkers associated with trained immunity can lead to novel diagnostic opportunities. Targeting metabolic and epigenetic pathways, as well as regulating the intestinal microbiota, is a promising therapeutic approach that could enhance the effectiveness of treatments for colorectal cancer while minimizing adverse effects on the immune system. Nevertheless, it is necessary to maintain a delicate equilibrium to suppress pathological inflammation without compromising protective immune responses. In general, trained immunity may represent a potentially relevant mechanistic link between chronic inflammation and colorectal cancer; however, its role remains context-dependent and not yet fully defined. Full article

Accounting for over 1.2 million new diagnoses worldwide in 2022, non-melanoma skin cancer (NMSC) represents the most common human cancer, predominantly manifesting as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). NMSC serves as a powerful natural model for studying how environmental exposure, the exposome, reprograms the epigenome to drive carcinogenesis. Chronic ultraviolet radiation (UVR), the dominant risk factor, induces DNA damage and inflammation that dysregulate epigenetic enzymes (e.g., DNMTs, HDACs). These effects are layered with perturbations from β-HPV infection and cutaneous dysbiosis, altering DNA methylation, histone modifications, and non-coding RNA and miRNA expression in a multistep carcinogenic process. This review synthesizes the central role of epigenetic regulation as the critical interface between genetic susceptibility and cumulative exposome factors in NMSC pathogenesis. We integrate how UVR, HPV, and inflammation converge to remodel the keratinocyte epigenome. Finally, we evaluate the translational potential of this knowledge for refined risk stratification through epigenetic biomarkers and discuss emerging therapeutic strategies, including epidrugs, that target these dysregulated pathways for advanced NMSC management. Full article

Oral cancer remains a major global health problem with high morbidity and mortality rates, and despite advances in therapeutic approaches, challenges persist in early diagnosis and effective disease management. MicroRNAs (miRNAs) are endogenous, small non-coding RNAs that regulate gene expression at the post-transcriptional level and play fundamental roles in maintaining cellular homeostasis, as well as in the initiation and progression of multiple malignancies, including oral cancer. Dysregulation of miRNAs contributes to oral carcinogenesis by modulating key cellular processes such as cell proliferation, apoptosis, invasion, metastasis, and angiogenesis. Altered miRNA expression profiles have been consistently identified in oral cancer tissues and body fluids, including saliva and blood, supporting their potential utility as reliable biomarkers for early detection, prognosis, and disease monitoring. Circulating miRNAs, in particular, represent a promising non-invasive diagnostic tool for assessing disease progression and therapeutic response. Moreover, miRNAs are actively involved in regulating sensitivity and resistance to chemotherapy and radiotherapy, with specific miRNAs either enhancing treatment efficacy or promoting therapeutic resistance. This review aims to highlight the critical role of miRNAs in oral cancer pathogenesis, diagnosis, prognosis, and treatment, exploring their potential as biomarkers and therapeutic targets to improve early detection, patient outcomes, and personalized treatment strategies. Full article

Colorectal cancer (CRC) remains one of the most prevalent malignancies worldwide and is the second largest contributor to both incidence and mortality, underscoring the urgent need for effective prevention strategies. This comprehensive review provides the most up-to-date evidence on the protective role of plant-based dietary patterns against CRC carcinogenesis, with particular emphasis on underlying cellular and molecular level mechanisms. Accumulating research demonstrates that plant-based foods, rich in dietary fibre, polyphenols, and multiple other bioactive compounds, promote gut microbial eubiosis, support immune regulation, and modulate adipose tissue homeostasis. These effects are accompanied by intestinal barrier integrity, enhanced production of short-chain fatty acids, and the induction of apoptosis in malignant cells. Moreover, plant-derived nutrients reduce the abundance of pro-inflammatory microbial taxa, decrease oxidative, nitrosative and carbonyl stress, and downregulate pro-inflammatory cytokines and signalling pathways, implicated in tumourigenesis. As a result, plant-based dietary patterns have high potential to reduce CRC risk through modulating the intricate interplay between epigenetics, inflammation, immune dysregulation, metabolic and hormonal disruptions, and gut microbiota, suggesting a highly promising, cost-effective and equitable strategy for CRC prevention. Full article

Background: YES1 is an Src family non-receptor tyrosine-protein kinase that regulates cell growth, migration, survival, and oncogenic signaling. Although YES1 activation mechanisms and substrates have been extensively studied, its phosphosite-specific regulation across diverse biological contexts remains poorly understood. Methods: We performed a large-scale integrative analysis of 3825 publicly available human mass spectrometry-based phosphoproteomic datasets to map YES1 phosphorylation events. Co-modulation, co-occurrence, evolutionary conservation, and disease-association analyses were conducted to characterize the functional and clinical relevance of site-specific YES1 phosphorylation. Results: Y426 emerged as the predominant YES1 phosphosite across diverse biological conditions, localized within the activation loop of the kinase domain and conserved across Src family kinases. Co-modulation analysis identified 421 positively and 102 negatively associated phosphosites enriched in biological processes related to cell cycle regulation, transcription, cytoskeletal remodeling, apoptosis, and carcinogenesis. Among these high-confidence protein phosphosites, we identified 24 binary interactors, 5 upstream regulators, and 8 candidate downstream substrates. Comparison with DisGeNet cancer biomarkers showed overlap between YES1-associated phosphoproteomic signatures and site-specific oncogenic markers across multiple cancers, such as breast cancer, colorectal cancer, leukemia, and lung adenocarcinoma. Conclusions: This study provides a systems-level, phosphosite-focused view of YES1 signaling and supports a central regulatory role for Y426 within global phosphoregulatory and cancer-associated networks. Full article