Search Results (461)

Human papillomavirus (HPV) infection is a leading cause of cervical cancer and a significant contributor to anogenital and oropharyngeal malignancies worldwide. While the oncogenic functions of HPV oncoproteins E6 and E7 in disrupting nuclear tumor suppressor pathways are well established, their influence on mitochondrial biology has only recently emerged as a critical facet of HPV-driven carcinogenesis. This review synthesizes current evidence on the qualitative and quantitative alterations of mitochondrial DNA (mtDNA) and their functional consequences in HPV-associated cancers. We discuss how E6 and E7 modulate mitochondrial dynamics, bioenergetics, and redox balance, contributing to metabolic reprogramming, resistance to apoptosis, and adaptation to tumor microenvironmental stress. We also examine the clinical significance of mtDNA mutations, deletions, and copy number variations as potential biomarkers for diagnosis, prognosis, and therapy response. Advances in multi-omics approaches, high-throughput sequencing, and patient-derived organoid models have accelerated the exploration of mitochondria as therapeutic targets. Integrating mitochondrial profiling into HPV-related cancer research holds promise for identifying novel metabolic vulnerabilities and guiding the development of mitochondria-directed treatment strategies. Full article

Colitis-associated colorectal cancer (CAC) represents a distinct subtype of colorectal malignancy that arises in the setting of chronic inflammatory bowel disease (IBD). Unlike sporadic colorectal cancer, CAC develops through inflammation-driven molecular pathways, in which epigenetic alterations play a pivotal role in tumor initiation and progression. This review highlights the major epigenetic mechanisms implicated in CAC, including DNA methylation, histone modifications, and microRNA (miRNA) dysregulation. Aberrant DNA methylation patterns, such as promoter hypermethylation of tumor suppressor genes and global hypomethylation, contribute to genomic instability and altered gene expression. In parallel, inflammation-induced changes in histone configuration modulate chromatin accessibility and transcriptional activity of key oncogenic and tumor-suppressive pathways. Furthermore, deregulated miRNAs influence multiple aspects of CAC pathogenesis by targeting genes involved in inflammation and tumor progression. Understanding these epigenetic processes provides valuable insights into the development of colorectal malignancy and identifies potential biomarkers for early detection and intervention in colitis-associated colorectal cancer. Full article

Background: Genetic mutations have proven to be the epicenters of cancer and disease progression. Traditional WXS sequencing and BLOSUM scoring can be used to infer the evolutionary conservation of amino acid substitutions, though these approaches are not informed by probable base pair sequence changes. Within gene mutation analysis, most tools focus on amino acid conservation or codon switching independently, limiting their ability to contextualize observed mutations against stochastic mutational processes. In the clinical setting, variants of unspecified significance remain difficult to interpret, as clinicians are often unable to determine whether observed mutations arise from oncogenic selection or from stochastic mutational degradation. Methods: We analyzed mutation sequences from the TCGA BRCA cohort for TP53 and PIK3CA and developed a model that integrates BLOSUM scoring with statistical modeling of base pair changes to evaluate deviation from codon-aware neutral expectations. Observed mutational distributions were compared against a stochastic neutral model to assess statistical significance. Results: Within the TCGA BRCA cohort, TP53 mutations were significantly more evolutionarily radical than expected under the codon-aware neutral model, while PIK3CA mutations were significantly more evolutionarily conservative, as determined using chi-square testing. These opposing patterns are consistent with the distinct functional roles of TP53 and PIK3CA in oncogenesis, where TP53 is inhibited through disruptive loss-of-function mutations, whereas PIK3CA is recurrently mutated in a manner that preserves protein structure and promotes constitutive pathway activation. This contrast reflects selective pressure toward disabling tumor suppressor function while maintaining persistent oncogenic signaling. Conclusions: Codon-aware neutral modeling provides a statistical framework for distinguishing mutations that deviate from stochastic expectations and may aid in the interpretation of variants of unspecified significance. By contextualizing mutational severity relative to neutral processes, this approach offers insight into tumor evolution and may support prognostic assessment without relying on predefined gene-level neutrality. Full article

ARID1A, a key subunit of the SWI/SNF chromatin remodeling complex, plays a context-dependent function in cancer, acting both as a tumor suppressor and, in certain conditions, as an oncogene. ARID1A, as a tumor suppressor, maintains transcriptional regulation, genomic stability, and cellular differentiation. In breast cancer, ARID1A loss-of-function leads to dysregulation of cell cycle checkpoints and impaired DNA repair and promotes epithelial-to-mesenchymal transition (EMT), jointly accelerating tumor proliferation and increasing therapeutic resistance. Notably, context-dependent ARID1A loss-of-function often concurs with activation of the PI3K/AKT signaling pathway and corresponds with poor prognosis. On the contrary, aberrant ARID1A overexpression can provoke oxidative stress and agitate the cytochrome P450 system, potentially facilitating early tumorigenesis. Consequently, understanding ARID1A’s dual and context-dependent role highlights its potential as a biomarker and therapeutic target in precision oncology. Full article

The Sprouty (SPRY) proteins are evolutionarily conserved modulators of growth factor-induced signaling pathways. The four different SPRY isoforms (SPRY1-4) are implicated in different types of cancer, acting as oncogenes or tumor suppressors depending on the SPRY isoform and the malignancy. Despite being tumor suppressors in many types of cancer, SPRY1 is an oncogene in rhabdomyosarcoma, SPRY2 in colorectal cancer, and SPRY4 in gastric cancer. In this review, we summarize the current literature about the functions of SPRY1-4 in glioblastoma (GB) and neuroblastoma (NB). To further delineate the effects of SPRY1-4 in the tumorigenesis of the nervous system, we analyzed the association of SPRY1-4 with the overall and event/progression-free survival of patients with pediatric and adult glioma, GB, and NB using public datasets. Together, there is evidence that SPRY1 and -2 are oncogenes in GB, whereas the role of SPRY3 and -4 in GB is not well defined. In NB, SPRY2 acts as a tumor suppressor, whereas the effects of SPRY1, -3, and -4 in NB have not been investigated so far, although the survival analysis revealed increased survival of NB patients with low SPRY3 levels in different datasets. Thus, this review demonstrates the requirement for further studies about the functions of the SPRY proteins in tumors of the nervous system to define their clinical relevance as potential therapeutic targets in the future. Full article

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer arising within the liver from the bile ducts, and it is characterized by limited therapeutic options and a poor prognosis. This neoplasm exhibits both high intra-tumor and inter-tumor heterogeneity and many oncogenic and tumor suppressor genes are involved in its development and progression. Here, we summarize the major pathways and driver genes involved in the genesis and progression of iCCA, with a special look at their potential therapeutic values. We approach not only the well–known FGFR, IDH and HER2 alterations but also delve into less known cellular pathways such as cell surface receptors, cellular signaling pathways, tumor suppressor genes and metabolic pathways. The aim of our review is therefore not only to summarize the available evidence on singular pathways/alterations but also to foster and promote new investigations into lesser known alterations that could be present in each singular iCCA case. Full article

Redox imbalance and epigenetic dysregulation, which both contribute to tumor initiation, survival, and resistance to therapy, are intimately linked to the progression of cancer. Reactive oxygen species (ROS) have two contrasting effects: at moderate concentrations, they promote angiogenesis and oncogenic signaling, whereas at high concentrations, they trigger apoptosis. Oxidative stress alters histone modifications, DNA methylation, and non-coding RNA (ncRNA) expression, reshaping the epigenetic landscape and supporting malignant phenotypes. Plant-derived antioxidants, including flavonoids, polyphenols, alkaloids, and terpenoids, act as dual modulators of cancer biology. They scavenge or regulate reactive oxygen species (ROS), restore redox balance, activate tumor suppressor pathways, inhibit oncogenic mechanisms, and reverse abnormal epigenetic marks. Compounds such as resveratrol, curcumin, epigallocatechin gallate (EGCG), quercetin, and sulforaphane modulate DNA methyltransferases (DNMTs), histone deacetylases (HDACs), and non-coding RNA networks, and can enhance chemotherapy and radiation therapy. Despite promising mechanisms, challenges remain in translational efficacy, optimal dosing, and bioavailability. This review emphasizes the potential of plant-derived antioxidants as precision oncology adjuncts and highlights the need for biomarker-guided strategies, nano-delivery systems, and clinical validation to fully realize their therapeutic benefits. Plant-derived antioxidants mitigate ROS-induced oncogenic signaling, as evidenced by in vitro and clinical models. 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

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by uncontrolled proliferation of myeloid cells. MicroRNAs (miRNAs), small noncoding RNAs, regulate post-transcriptional gene expression by degrading target mRNAs or repressing translation. Dysregulated miRNA expression has been implicated in various malignancies, including CML, where they can function as oncogenes or tumor suppressors. This study aimed to investigate the relationship between miR-122-5p and cell division cycle 25A (CDC25A) in CML and to elucidate the regulatory mechanisms of miR-122-5p. This study integrates bioinformatics analysis with in vitro RT-qPCR validation in K562 chronic myeloid leukemia cells to explore the potential regulatory relationship between miR-122-5p and CDC25A. mRNA expression profiles were retrieved from the GSE100026 dataset in the Gene Expression Omnibus (GEO), and differentially expressed genes were identified using GEO2R. Quantitative real-time PCR (RT-qPCR) was performed to measure miR-122-5p, CDC25A, and cyclin-dependent kinase 4 (CDK4) expression levels. Bioinformatics analyses (miRNeT, miRDIP, TargetScan, BioGPS, GeneMANIA, STRING) were applied to predict molecular interactions and functional pathways. Public RNA-seq datasets and in silico tools were used to prioritize candidates; RT-qPCR in a single CML cell line (K562) provided in vitro expression validation. In K562 cells, miR-122-5p expression was significantly reduced, while CDC25A and CDK4 were markedly upregulated. Bioinformatics tools confirmed CDC25A as a potential miR-122-5p target. Functional enrichment indicated CDC25A involvement in cell cycle regulation and apoptosis. These findings suggest that miR-122-5p functions as a tumor suppressor in CML by targeting CDC25A. Modulating the miR-122-5p/CDC25A axis may provide potential molecular targets for inhibiting CML progression through regulation of cell cycle pathways. Findings are exploratory and based on bioinformatics with limited in vitro expression confirmation; functional studies are required to establish causality. Full article

Uterine leiomyosarcoma (uLMS) is a rare, highly aggressive malignancy of uterine smooth muscle, associated with early metastasis, frequent recurrence, and poor prognosis. Accurate preoperative diagnosis remains difficult given that clinical and radiologic features often overlap with benign leiomyomas, and no reliable biomarkers are currently available. This review summarizes recent evidence on the role of microRNAs (miRNAs) in the biology and clinical management of uLMS. Literature from molecular and translational studies was examined to identify dysregulated miRNAs, their target pathways, and potential diagnostic and therapeutic applications. uLMS displays a characteristic miRNA profile, including downregulation of tumor-suppressive miRNAs such as the miR-29 and miR-200 families and upregulation of oncogenic miRNAs including miR-21 and the miR-183~96~182 cluster, leading to activation of PI3K/AKT/mTOR signaling and epithelial–mesenchymal transition (EMT). Circulating and tissue miRNAs show promise as minimally invasive biomarkers for differentiating uLMS from leiomyomas, predicting prognosis, and guiding therapy. Emerging therapeutic approaches aim to restore the tumor-suppressive miRNAs or inhibit oncogenic ones using mimics or antagomiRs. Overall miRNAs represent critical regulators of uLMS pathogenesis and hold significant potential for precision diagnosis, prognostication, and targeted therapy, though larger validation studies and improved delivery systems are required before clinical translation. Full article

Glioblastoma (GBM), formerly referred to as glioblastoma multiforme, represents the most prevalent and aggressive form of glioma, predominantly affecting the aging population. Despite considerable advances in recent years in elucidating its pathogenesis and developing novel immunotherapeutic approaches, the overall survival rate for patients with this central nervous system (CNS) neoplasm remains dismally low. Consequently, there is an urgent and unmet need to identify and characterize additional therapeutic targets that could be employed synergistically with existing treatment modalities to enhance both survival outcomes and quality of life. Among the emerging areas of investigation, substantial interest has been directed toward aging-associated molecular signaling mechanisms that also constitute key oncogenic pathways in GBM. These include aberrant growth factor signaling, hyperactivation of the PI3K/AKT/mTOR axis, and inactivation of critical tumor suppressor pathways such as p53 and retinoblastoma (RB). The dysregulation of these signaling cascades results in profound disturbances of essential cellular homeostatic processes, notably autophagy and cellular senescence, which are intimately involved in both tumor initiation and progression. This review aims to delineate the complex interplay between autophagy and cellular senescence within the context of aging-related GBM pathogenesis. Furthermore, it explores the relevant intracellular signaling transduction mechanisms that govern these processes and discusses prospective therapeutic strategies. Full article

Pulmonary carcinoma remains a highly aggressive malignancy driven by complex signaling and epigenetic dysregulation. This study investigates a novel oncogenic pathway involving the Mg^2+/Mn²⁺-dependent protein phosphatase 1B PPM1B/myosin phosphatase (MP)/protein arginine methyltransferase 5 (PRMT5) axis, which promotes carcinogenesis by symmetrically dimethylating histone H2A and suppressing tumor suppressor genes. We hypothesized that loss of PPM1B would activate this pathway and drive tumorigenesis. Western blotting, PCR, and immunohistochemistry revealed a significant reduction in PPM1B expression in both squamous cell carcinoma (SCC) and human lung adenocarcinoma (ADC) compared to normal lung tissues, which correlated with worse patient survival. Despite an increase in total MYPT1, the regulatory subunit of MP, its inhibitory phosphorylation at Thr853 was significantly elevated in both tumor types. The inactivation of MP corresponded with a significant increase in the activating phosphorylation of PRMT5 at Thr80, especially in SCC, which was linked to a particularly poor prognosis. Downstream, this resulted in a dramatic elevation in the symmetric dimethylation of histone H2A, leading to decreased expression of retinoblastoma protein. Our findings demonstrate that decreased PPM1B expression drives the oncogenic activation of the MP/PRMT5 axis. This mechanism contributes to the aggressive nature of SCC, establishing PPM1B as a promising prognostic marker in lung cancer. Full article

Optineurin (OPTN) is a multifunctional adaptor protein that regulates diverse cellular processes, including inflammatory signaling, autophagy, vesicular trafficking, and immune responses. This multifaceted role of OPTN is made possible by the presence of a complex structure comprising multiple domains that interact with different proteins to exert various functions important for modulating key signaling processes. Mutations in OPTN are linked with several human pathologies including glaucoma, Paget’s disease of bone, Crohn’s disease, and neurodegenerative diseases such as amyotrophic lateral sclerosis, and dementia. Emerging evidence suggests that OPTN has a complex and context-dependent role in cancer biology as well. It is upregulated in pancreatic ductal adenocarcinoma and hepatocellular carcinoma but downregulated in lung and colorectal cancers, indicating its dual role as a potential oncogene or tumor suppressor depending on the cellular environment. Additionally, OPTN plays a critical role in preventing immune evasion in colorectal cancer by maintaining interferon-gamma receptor 1 (IFNGR1) expression and supporting dendritic cell-mediated T-cell priming, thereby enhancing antitumor immune responses. Despite its significance in oncogenic pathways and immune regulation, the therapeutic potential of targeting OPTN in cancer remains largely unexplored. This review aims to provide a comprehensive understanding of OPTN’s pleiotropic functions, highlighting its role in autophagy, inflammation, immune surveillance, and cancer progression. By elucidating its diverse regulatory mechanisms, we seek to encourage further research into the therapeutic implications of OPTN in cancer treatment and immunotherapy. Full article

Background: Non-small cell lung cancer (NSCLC) progression is driven by dysregulated competing endogenous RNA (ceRNA) networks, where non-coding RNAs sequester miRNAs to modulate oncogene expression. The tumor-suppressor miR-145 is frequently downregulated in NSCLC, but its lncRNA-mediated regulation remains incompletely characterized. Methods: Integrated transcriptomic analysis of NSCLC datasets (GSE135304: blood RNA from 712 patients; GSE203510: plasma miRNAs) was used to identify dysregulated genes (|log2FC| > 0.1, p < 0.05) and miRNAs (|log2FC| > 1, p < 0.05). Experimentally validated targets from miRTarBase/TarBase were intersected with dysregulated genes, followed by WikiPathways/GO enrichment. ceRNA networks were constructed via co-expression analysis. RT-qPCR validated miR-145-3p expression in A549/MRC-5 cells and NSCLC tissues. GEPIA assessed FN1/CCND1 clinical relevance. Results: We identified 8271 dysregulated genes and 52 miRNAs. miR-145-3p, critical in immune regulation, was significantly downregulated (log2FC = −1.24, p = 0.036). Intersection analysis revealed 27 miR-145-3p targets (e.g., FN1, CCND1, SMAD3) enriched in immune pathways (FDR < 0.05) and TGF-β-mediated EMT within the dysregulated geneset. Six immune-linked hub genes emerged. LncRNAs LOC729919 and LOC100134412 showed strong co-expression with hub genes and competitively bind miR-145-3p, derepressing the expression of the metastasis drivers FN1 (ECM regulator) and CCND1 (cell cycle controller). This ceRNA axis operates within a broader dysregulation of ATM-dependent DNA damage, Hippo signaling, and cell cycle pathways. RT-qPCR confirmed significant miR-145-3p suppression in NSCLC models (p < 0.05). GEPIA revealed a significant FN1-CCND1 co-expression (p = 0.0017). Conclusions: We characterize a novel LOC729919/LOC100134412–miR-145–FN1/CCND1 ceRNA axis in NSCLC pathogenesis. FN1’s prognostic value and functional linkage to CCND1 underscores its potential clinical relevance for therapeutic disruption. Full article

Genome editing technologies, including CRISPR/Cas9, TALENs, and ZFNs, offer promising approaches to disrupt HPV oncogenes E6 and E7, thereby restoring tumor-suppressor pathways. In this review, we summarize recent preclinical findings demonstrating selective apoptosis and tumor regression in HPV-positive cell and animal models, as well as early-phase clinical studies exploring local CRISPR-based therapies. We also compare the relative strengths and limitations of major editing platforms, discuss delivery strategies, and highlight their potential integration with immunotherapy and conventional treatments. While preclinical studies show encouraging efficacy (e.g., up to 60% tumor regression in xenograft models and marked reactivation of p53/pRb pathways), translation into routine practice remains limited by challenges such as efficient delivery, minimizing off-target effects, long-term safety, cost, and ethical considerations. Continued optimization of high-fidelity nucleases, tissue-specific delivery systems, and genotype-tailored guide RNAs will be essential. Genome editing therefore represents a potential future addition to the therapeutic landscape of HPV-related diseases, but substantial barriers must be addressed before clinical implementation. Full article