Search Results (9,329)

MicroRNAs (miRNAs) are key posttranscriptional regulators of gene expression that influence cancer initiation, progression, and therapeutic response. While most studies have focused on endogenous miRNAs, emerging evidence has highlighted the role of plant-derived miRNAs as exogenous dietary regulators capable of cross-kingdom gene modulation. This review summarises current knowledge regarding plant-derived miRNAs and their ability to regulate human cancer-related genes. Experimental findings indicate that plant miRNAs can withstand gastrointestinal digestion, enter the circulation, and regulate the expression of oncogenes, tumour suppressors, long noncoding RNAs, and immune checkpoint molecules via canonical RNA-induced silencing mechanisms. Specific examples include miR-156a, miR-159a-3p, miR-166a, miR-167e-5p, miR-171, miR-395e, miR-2911, miR-4995 and miR-5754, which exhibit anticancer activities across various cancer types and modulate key signalling pathways in mammalian cells, highlighting their potential as cross-kingdom regulators with therapeutic relevance. In addition to these characterised miRNAs, certain plant groups, which are rich in bioactive compounds, remain unexplored as sources of functional miRNAs, representing a promising avenue for future research. Collectively, these studies underscore the ability of plant-derived miRNAs to modulate mammalian gene expression and suggest their potential as diet-based or synthetic therapeutic agents. Further investigations into their bioavailability, target specificity, and functional relevance could inform innovative strategies for cancer prevention, integrating nutritional, molecular biological, and therapeutic approaches. Full article

The complex relationship between human cytomegalovirus (HCMV) and cancer has been of interest since the 1960s. As a highly prevalent human β-herpesvirus, HCMV establishes lifelong latency in CD34+ myeloid progenitor cells and has been implicated as an oncomodulatory virus in various cancers, including glioblastoma multiforme, breast, prostate, colorectal, and ovarian cancer (OC). Recently, discussions have emerged regarding the classification of HCMV as an eighth oncovirus due to the persistence of its nucleic acids and proteins in many tumour types. As one of the deadliest gynaecological cancers, OC is often characterised as the ‘silent killer’ with less than half of women surviving for 5 years, a rate that drops below 20% when detected at advanced stages. Reported effects of HCMV vary between cancers, likely due to differences in tumour type, viral strain, and disease stage. While HCMV infection has been linked to poor OC patient outcomes, its impact on the OC tumour microenvironment (TME) and immune system remains less understood. Investigating HCMV’s potential oncogenic role could provide critical insights into OC progression. This review discusses recent developments on HCMV’s multifaceted roles in OC, including strain heterogeneity, immunomodulation of the TME, dysregulation of inflammatory signalling pathways, and potential therapeutic approaches targeting HCMV in anti-cancer immunotherapies. Full article

SOX (SRY-related HMG-box) transcription factors are key regulators of embryogenesis and vascular development, with emerging roles in cancer biology. In non-small-cell lung cancer (NSCLC), the contributions of SOX18 and SOX30 remain insufficiently understood, particularly regarding their epigenetic regulation and network interactions with angiogenic and immune-modulatory pathways. We examined 800 NSCLC specimens (400 lung adenocarcinomas, 400 squamous cell carcinomas) using immunohistochemistry, RT-qPCR, Western blotting, and spatial transcriptomics to profile SOX18, SOX30, and related signaling partners (SOX7, SOX17, MEF2C—Myocyte Enhancer Factor 2C, VCAM1—Vascular Cell Adhesion Molecule 1, p-STAT3—Signal Transducer and Activator of Transcription 3). Epigenetic regulation was assessed via droplet digital methylation-specific PCR of promoter CpG islands, while functional validation employed adenoviral delivery of hsa-miR-24-3p in NSCLC cell lines and 3D spheroid cultures. SOX18 protein was markedly overexpressed in both NSCLC subtypes, despite reduced transcript levels and consistent promoter hypermethylation, suggesting post-transcriptional regulation. In contrast, SOX30 expression was uniformly downregulated at both mRNA and protein levels, frequently linked to promoter hypermethylation, especially in squamous carcinoma. Spatial transcriptomics revealed SOX18 enrichment at tumor cores and invasive borders, co-localizing with MEF2C, VCAM1, and p-STAT3 in vascular and stromal niches, while SOX30 expression remained low across all tumor regions. Functional assays demonstrated that hsa-miR-24-3p suppressed SOX18 expression and partially modulated SOX30 and MEF2C, reinforcing a miRNA-driven regulatory axis. In summary, SOX18 and SOX30 play divergent roles in NSCLC progression: SOX18 functions as a pro-oncogenic factor driving angiogenesis and tumor–stroma interactions, while SOX30 acts as an epigenetically silenced tumor suppressor. Regulation of SOX18 by miR-24-3p highlights a potential therapeutic vulnerability. These findings underscore the significance of SOX transcription factors as biomarkers and potential targets for novel treatment strategies in NSCLC. Full article

Melanoma cells in the brain may use similar mechanisms for adapting to injury and/or disease (that is, through continued reallocation of energy, matter, and information) as other cell types do to create an environment in which cancer cells can grow and sustain themselves within the confines of the brain. These adaptable mechanisms include the ability to reactivate dormant neural crest-derived migration and communication pathways. Unlike some other types of cancers that invade neural tissue as a simple invasion, melanomas are capable of achieving limited molecular, metabolic, and electrical similarity to the neural circuitry of the brain. Melanomas achieve this limited similarity through both vascular co-optation and mimicking synaptic functions, as well as through their engagement of redox-coupled metabolic pathways and feedback-regulated signal transduction pathways. The result is the creation of a metastable tumor–host system, where the relationship between tumor and host is defined by the interaction of stabilizing and destabilizing forces; forces that define the degree of coherence, vulnerability, and persistence of the tumor–host system. In this review, we integrate molecular, electrophysiological, and anatomical data to develop a single unifying hypothesis for the functional integration of melanoma cells into the neural tissue of the brain. Additionally, we describe how neural crest-based regulatory pathways are reactivated in the adult brain and how tumor–host coherence is developed as a function of the shared thermodynamic and informational constraints placed on both tumor and host. We also describe how our proposed conceptual model allows for the understanding of therapeutic interventions as selective disruptions of the neural, metabolic, and immunological couplings that support metastatic adaptation. Full article

Breast cancer (BC) is a heterogeneous disease with distinct molecular subtypes that exhibit variable immune responses and metabolic profiles. Recent studies have suggested that immunometabolic pathways play a role in tumor progression and treatment resistance. This study investigates the expression patterns of ALKBH7 and NLRP3 across BC molecular subtypes and explores their relationships with clinicopathological parameters and potential immunometabolic profiles. A total of 118 BC patients were classified into HER2+, TNBC, Luminal A, and Luminal B subtypes. Gene expression levels of ALKBH7 and NLRP3 were analyzed using quantitative real-time PCR (qRT-PCR), and correlations with clinical markers were assessed. ALKBH7 and NLRP3 expression levels varied significantly between subtypes, with the highest expression observed in HER2+ tumors. Strong positive correlations were found between ALKBH7 and NLRP3 in all subtypes, particularly in HER2+ (r = 0.812, p < 0.001). Additionally, NLRP3 correlated with Ki-67 in Luminal B tumors, indicating a link between inflammation and proliferative capacity. These findings suggest that ALKBH7 may function as a dual-role biomarker involved in metabolic adaptation and immune signaling in BC. The strong co-expression of ALKBH7 and NLRP3 suggests a functional association between these molecules that may be critical in shaping the tumor microenvironment. This co-expression set, particularly in aggressive subtypes (HER2+ and TNBC), warrants further mechanistic validation as a potential prognostic marker and a novel therapeutic vulnerability. Full article

Melanocyte signaling through the MAPK pathway is orchestrated by NRas and relayed downstream via multiple effectors, such as RAF, Ral, and PI3K. In spite of their significance, the molecular mechanisms of signaling relay by NRas, their dynamics, and their potential as therapeutic targets remain unclear. Using multi-color single molecule localization microscopy (PALM and dSTORM), we resolved the mutual nanoscale organization of NRas, PI3K, and BRAF at the plasma membrane of fixed and live melanoma cells. Surprisingly, NRas and its oncogenic mutation Q61R colocalized with PI3K in mutual nanoclusters, where BRAF was also frequently present. In live cells, NRas and PI3K co-clustering declined, yet persisted over minutes. Clinically relevant perturbations revealed unexpected crosstalk within these nanoclusters and consequently, between the MAPK and PI3K pathways. Specifically, overexpression of the Ras binding domain (RBD) and PI3K inhibition by wortmannin disrupted NRAS-PI3K interactions, and reduced both pAKT and pERK levels and cancer cell proliferation. MEK inhibition with trametinib resulted in similar, yet more pronounced effects. Thus, our findings provide novel insights into NRAS-mediated signaling through nanoscale clusters and underscore their potential as therapeutic targets. Full article

Background/Objectives: Pulmonary fibrosis (PF) and lung cancer (LC) are major global health challenges that share several pathogenic mechanisms despite their distinct clinical features. PF leads to progressive fibrotic remodeling and respiratory decline, while LC is characterized by uncontrolled proliferation, invasion, and metastasis. Growing evidence shows that PF markedly increases the risk of LC development. This review aims to clarify the convergent molecular and cellular mechanisms that link fibrogenesis to tumorigenesis. Methods: Published studies exploring shared pathogenic pathways, molecular signaling networks, immune microenvironment alterations, and mitochondrial and genomic disturbances in PF and LC were systematically examined and integrated to identify common mechanisms contributing to fibrosis-associated carcinogenesis. Results: Findings highlight several overlapping processes between PF and LC, including oxidative stress, genomic instability, dysregulated DNA damage repair, immune microenvironment remodeling, mitochondrial dysfunction, and alterations in the ubiquitin–proteasome system. These aberrations drive chronic inflammation, epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and other hallmarks shared by both diseases. Key signaling pathways—such as transforming growth factor-β (TGF-β), programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1), and tumor microenvironment–mediated immune evasion—further contribute to disease progression and increased LC risk in PF patients. Conclusions: Integrating molecular and pathological insights reveals a strong biological continuum between PF and LC. Understanding these convergent mechanisms may facilitate the identification of diagnostic biomarkers and therapeutic targets, ultimately helping to mitigate PF-associated lung carcinogenesis. Full article

The treatment of gynecological cancers is challenging because they are often diagnosed at the advanced stages. Furthermore, available chemotherapeutics increasingly imply the development of resistance in cancer patients. This necessitates the search for alternative solutions that could be used in therapy. One of the possibilities to consider is the use of pentacyclic triterpenoids. They are naturally occurring compounds characterized by a wide range of biological activities. They can also be modified to improve their pharmacological properties. Terpenoids based on oleanane, ursane, and lupane skeletons can modulate the numerous processes occurring in both normal and transformed cells. To develop effective anti-cancer therapy, it is essential to understand the processes regulating the progression and suppression of a given type of cancer. For this reason, it is necessary to assess the influence of the tested compounds on cellular processes such as the cell cycle, epithelial–mesenchymal transition, autophagy, and apoptosis. This article summarizes available information on the effects of pentacyclic triterpenoids on the PI3K/AKT/mTOR, MAPK/ERK, NF-κB, JAK/STAT, Notch, HIF-1α, TGF-β, Wnt/β-catenin, Hippo, and Hedgehog signaling pathways in ovarian cancer cells. Full article

Cancer has become the second leading cause of death globally and is a big threat to human health. The development of new anticancer drugs and the elucidation of the signaling pathways of bioactive compounds are still effective strategies to address the current challenges in the clinical treatment of cancer. Dietary compounds are composed of a variety of effective ingredients, which have become an important source for the development of novel candidates for the treatment of cancer. These bioactive ingredients often carry the characteristics of low side effects, multi-target, and economic savings and hence attract more and more scholars’ research interests in them. Dandelion, one of the important medicinal and edible plants, is effective in anticancer, inhibition of bacterial growth, hypoglycemic, and anti-inflammation, as well as antioxidant. Growing evidences from modern pharmacological research demonstrate the notable anticancer effects of dandelion. Bioactive components from dandelion are effective in inhibiting the occurrence and progression of various cancers, such as breast, lung, and liver cancers. Hence, the chemical composition, anticancer activities, and signaling pathways in cancer cells treated with bioactive components from dandelion are summarized in this review. We aim to provide more pharmacological evidence and scientific references for further research and development of dandelion for cancer treatment. Meanwhile, we anticipate that some novel candidates with high efficacy and low toxicity for anticancer might be developed from dandelion in future research on this plant. Full article

Background: The Hippo signaling pathway, a highly conserved regulatory cascade, regulates tissue homeostasis, organ size, and tumor suppression. Dysregulation of this pathway contributes to oncogenesis in various human malignancies; however, its clinicopathologic relevance in cervical cancer has not been completely elucidated. Therefore, this study aimed to investigate the expression patterns of key Hippo pathway proteins and analyze their associations with tumor behavior and clinicopathologic features in cervical carcinoma. Materials and Methods: Ninety-nine cervical cancer specimens obtained from hysterectomies performed at Gyeongsang National University Hospital (2012–2019) were retrospectively analyzed. Immunohistochemical staining for Yes-associated protein (YAP), phosphorylated YAP (p-YAP), mammalian sterile-20-like kinase-1 (MST1), and large tumor suppressor kinase-1 (LATS1) was performed on tissue microarrays. Chi-square or Fisher’s exact tests and logistic regression were employed for assessing associations between marker expression and clinicopathologic variables. Functional validation was conducted via small interfering RNA-mediated YAP knockdown in Caski cervical cancer cells, with reverse transcription-polymerase chain reaction, Western blotting, and wound-healing assays assessing YAP suppression and cell migration. Results: YAP and p-YAP were expressed in 71.8% and 62.6% of tumors, respectively; MST1 in 82.8%; and LATS1 in 22.2%. YAP and p-YAP overexpression was correlated with larger tumor size (p = 0.013 and p = 0.011) and higher International Federation of Gynecology and Obstetrics stage (p = 0.007 and p < 0.001). YAP and p-YAP expression was positively correlated (odds ratio, 4.34; 95% confidence interval, 1.70–11.61). MST1 or LATS1 expression demonstrated no significant associations. In vitro, YAP silencing decreased mRNA and protein expression levels and significantly impaired cell migration, supporting its role in tumor aggressiveness. Conclusions: YAP and p-YAP overexpression are associated with advanced stage and larger tumor size in cervical cancer, indicating Hippo pathway dysregulation. YAP functional suppression attenuated migratory capacity, highlighting YAP as a promising prognostic biomarker and therapeutic target. Full article

Breast cancer remains the leading cause of cancer-related death in women worldwide. This disease is characterized by its molecular and phenotypic heterogeneity, which hinders the development of effective therapies. While two-dimensional (2D) monolayer cell cultures are widely used, they are insufficient to reproduce the characteristics of the tumor microenvironment, thus limiting our understanding of cancer biology. In this context, three-dimensional (3D) models have emerged as representative tools that more accurately reproduce tissue architecture, cell signaling, and nutrients and oxygen gradients. These cellular models offer greater similarity to primary tissues, improving the study of relevant biological processes. Although 3D cultures provide numerous advantages in cancer research, there is no unified model that standardizes the matrix type and parameters such as gelation time or porosity, hindering the reproducibility and interpretability of the data. This review integrates evidence from various studies to evaluate the effect of epigenetic variations generated by 3D culture methods, which are regulated by mechanotransduction and, consequently, by signaling pathways such as integrin/FAK-ILK/Rho-YAP derived from interactions of cells with extracellular matrix-enriched scaffolds. This affects processes such as DNA methylation, histone coding, and the regulation of non-coding RNAs such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in different molecular subtypes of breast cancer. Overall, the evidence highlights that 3D culture methods are not equivalent but rather generate distinct epigenetic signatures at the non-coding RNA level that influence the proliferation, differentiation, therapeutic resistance, and metastatic potential of tumor cells. Furthermore, the evidence suggests that histone coding patterns, primarily through the reduction of acetylation marks, are conserved regardless of the type of 3D culture. In summary, the study highlights that the microarchitectural and compositional characteristics of 3D scaffolds are key determinants of epigenetic plasticity. Full article

C-reactive protein (CRP) is a well-known acute phase reactant and putative biomarker for advancing and chronically established inflammation. Its biological activity across its multiple isoforms plays various roles in the initiation, potentiation, and resolution of inflammation. Its molecular signaling within the tissue microenvironment regulates cell–cell communication across cell types (e.g., epithelial cells, endothelial cells, fibroblasts, adipocytes, and immune cells) and affects the development of conditions such as cancer that are subject, at least in part, to inflammatory signaling. Considering the dynamic nature of CRP in modulating disease progression, and the growing evidence of the context-dependent direct molecular activity of CRP on regulating intra- and inter-cellular signaling, it is critical to further understand how this integral molecule alters cell signaling pathways. Although the ability of CRP to directly interact with some extracellular matrix proteins involved with inflammation and disease has been reported as early as the mid-1980s, recent advances in unbiased proteomics have revealed a broader interactome of protein–protein interactions (PPIs) involving CRP. The present study evaluates the CRP PPIs identified to date and explores the potential novel regulatory capacity of CRP on multiple key cellular functions in metabolism and cell–cell signaling, offering an updated framework of the possible biological activities of CRP relevant to tumorigenic processes. Full article

MicroRNA-221 (miR-221), a conserved small non-coding RNA, acts as a pivotal modulator of biological processes across multiple organ systems, the dysregulation of which is closely linked to the pathogenesis of various human diseases. This review systematically summarizes its multifaceted roles in cancer, cardiovascular diseases (CVDs), neurological disorders, digestive system diseases, respiratory conditions, and adipose-endocrine dysfunction. In cancer, miR-221 exerts context-dependent oncogenic/tumor-suppressive effects by targeting phosphatase and tensin homolog (PTEN), cyclin-dependent kinase inhibitor 1c (CDKN1C/p57), and BCL2 modifying factor (Bmf), thereby regulating cell proliferation, invasion, stemness, and resistance to cancer therapy; it also serves as a non-invasive biomarker for glioma, papillary thyroid carcinoma, and colorectal cancer. In the cardiovascular system, it balances antiviral defense in viral myocarditis, modulates ventricular fibrotic remodeling in heart failure, and regulates endothelial function in atherosclerosis, with cell-type/ventricle-specific effects. In neurological disorders, it protects dopaminergic neurons in Parkinson’s disease and modulates microglial activation in epilepsy. It also regulates hepatic pathogen defense and intestinal mucosal immunity. Mechanistically, miR-221 alters cellular phenotypes by targeting tumor suppressors or signaling components (e.g., PI3K/AKT, TGF-β/suppressor of mothers against decapentaplegic homolog(SMAD), Wnt/β-catenin). Therapeutically, miR-221-targeting strategies show preclinical promise in cancer and CVDs. Despite this progress, further studies are needed to resolve context-dependent functional discrepancies, validate biomarker utility, and develop cell-specific delivery systems. This review provides a framework to understand its pathophysiologcial roles and potential application as a biomarker and therapeutic target. Full article

Background/Objectives: This NGS-based study sought to identify novel molecular markers for prostate cancer by comparing miRNA expression in cancer and benign prostatic hyperplasia (BPH) tissues. Methods: Using high-throughput sequencing and stringent statistical criteria, the study identified eleven significantly dysregulated miRNAs (five downregulated, six upregulated) that differentiate the two conditions. Enrichment analyses linked these miRNAs to several key cancer-associated pathways, including PI3K–Akt and ErbB signaling. Results: Crucially, the protein vesicle-associated membrane protein-associated protein B (VAPB) was pinpointed as a central hub, regulated by three downregulated miRNAs (miR-143-3p, miR-221-3p, and miR-222-3p). Since VAPB has not been widely studied in prostate cancer, it represents a promising, novel candidate for both diagnosis and therapeutic targeting. Conclusions: Our NGS-based analysis revealed a distinct miRNA expression signature that differentiates prostate cancer from BPH. The downregulation of several tumor-suppressive miRNAs (with concomitant upregulation of oncogenic miRNAs) in prostate cancer may contribute to malignancy—including the de-repression of novel targets like VAPB, which we identify as a promising new biomarker and therapeutic target. Full article

Background: Cholangiocarcinoma (CCA) is an aggressive cancer of biliary tract with poor prognosis and limited therapeutic alternatives. While targeted medicines only benefit a small subset of patients with specific genetic modifications, conventional chemotherapy offers negligible survival advantages. There is an urgent need for novel medicines with multi-target action to combat the diverse and treatment-resistant characteristics of CCA. Methods: An integrative computational strategy combining drug-likeness evaluation, target prediction, network pharmacology, Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analyses, and molecular docking was employed to elucidate the pharmacological profile of medicarpin, a natural pterocarpan derived from Dalbergia species. Overlapping targets between medicarpin and CCA-related genes were analysed to construct a protein–protein interaction (PPI) network and identify hub genes. Results: Forty-four overlapping targets were identified, with mTOR, SRC, PIK3CA, and CCND1 emerging as central nodes within the network. Enrichment analyses revealed significant involvement in carcinogenic pathways, including PI3K–Akt/mTOR, ErbB signalling, apoptosis regulation, and drug resistance. Molecular docking demonstrated a stable binding of medicarpin within the catalytic pocket of mTOR (binding energy −9.6 kcal/mol), supported by multiple hydrogen bonds and hydrophobic interactions with key residues essential for kinase activation. Conclusions: This study provides systems-level evidence that medicarpin exerts polypharmacological activity against CCA, with mTOR indicated as a possible mechanistic hub. These findings highlight medicarpin’s potential as a promising multi-target therapeutic candidate and underscore the value of natural compounds in expanding treatment strategies for cholangiocarcinoma. Full article