Search Results (329)

Background: Breast cancer susceptibility gene 1 (BRCA1) is a pivotal regulator of DNA repair, and its loss through germline mutations is strongly linked to the development of aggressive breast cancers with characteristic clinical and pathological features. Beyond genetic disruption, epigenetic silencing via promoter hypermethylation has emerged as a non-mutational mechanism of tumour suppressor inactivation and a potential biomarker for guiding therapeutic decisions. Here, we investigate BRCA1 promoter methylation, its impact on gene expression, and its association with clinicopathological features in a cohort of African women with breast cancer. Methods: Matched tumour and adjacent normal tissues from 27 Black African women with breast cancer were analysed for BRCA1 promoter methylation and gene expression using bisulfite pyrosequencing and quantitative real-time PCR. Associations with clinicopathological variables were assessed using Spearman’s correlation analyses. Results: Five CpG sites within the BRCA1 promoter were significantly hypermethylated in breast tumours compared with matched adjacent normal tissues and showed an inverse association with BRCA1 mRNA expression. Elevated promoter methylation was enriched in hormone receptor-negative and triple-negative breast cancer subtypes and was not influenced by neoadjuvant chemotherapy. BRCA1 promoter methylation occurred independently of BRCA1 mutational status. No significant associations were observed between BRCA1 methylation and age, body mass index, smoking status, or alcohol consumption. Conclusions: Our findings provide evidence of BRCA1 epigenetic silencing in breast tumours from African women, particularly within aggressive hormone receptor-negative subtypes. These results suggest that BRCA1 promoter methylation may represent a clinically informative biomarker for patient stratification and highlight the importance of validation in larger, population-representative cohorts before clinical translation. Full article

Background: T-cell-engaging bispecific antibodies (TCEs) have transformed haematological malignancy treatment (blinatumomab > 40% complete remission), yet solid tumour efficacy remains limited (<15% response rates) due to antigen heterogeneity, immunosuppressive microenvironments, and T-cell dysfunction. Systematic molecular engineering, biomarker-driven patient selection, and rational tumour microenvironment modulation are now collectively transforming TCEs from experimental agents into an adaptable platform therapy for solid tumours. Methods: Review of 55 phase I–III trials of CD3-based TCEs in solid tumours, including tarlatamab (DLL3-targeted, small-cell lung cancer) and xaluritamig (STEAP1-targeted, prostate cancer). Analysis of next-generation engineering strategies and resistance mechanisms via genomic and immunohistochemical data. Result: Response rates now approach ~40% in selected settings, marking an inflection point. In extensive-stage small-cell lung cancer, tarlatamab achieved ~40% responses with definitive survival benefit (phase III HR 0.60, 95% CI 0.47–0.77; p < 0.001; median OS 13.6 months). In metastatic castration-resistant prostate cancer, xaluritamig produced ~41% responses in heavily pretreated patients. Step-up dosing reduced severe cytokine release syndrome to <1% (as low as 0.6% with teclistamab), enabling outpatient administration. Neurological adverse events require monitoring but are less frequent than with cellular therapies. Together these results mark a decisive transition from proof-of-concept to clinically validated platform therapy. Discussion: Three resistance mechanisms limit durability: (i) antigen heterogeneity (28–60% of progressors develop antigen-negative subclones); (ii) immunosuppressive microenvironments (stromal barriers, myeloid-derived suppressor cells, hypoxia); (iii) T-cell exhaustion (PD-1/TIM-3/LAG-3 co-expression). Conclusions: Next-generation TCE platforms integrating conditional activation, cytokine payloads, and checkpoint modulation—deployed with biomarker-guided selection and TME-modulating combinations—represent a transformative therapeutic strategy. With tarlatamab’s phase III survival benefit establishing clinical proof-of-concept, and pivotal trials underway for xaluritamig and next-generation agents, TCEs are positioned to become standard-of-care platform therapies in biomarker-defined solid tumours by 2028–2030. Full article

Background: Exercise modulates the immune system and may enhance anti-cancer activity, offering potential synergy with cancer immunotherapy. Tumours with low immune cell infiltration (“cold” tumours) often respond poorly to immunotherapy and are associated with poor prognosis. Here, we demonstrate that exercise can reshape the immune landscape of tumours across the cold spectrum. Methods: C57BL/6 mice underwent orthotopic implantation of PANC02 (murine pancreatic adenocarcinoma) cells and BALB/c mice underwent intraperitoneal injections of AB-1 (murine mesothelioma) cells. Mice were then divided into groups; exercise with anti-Programmed Cell Death Protein 1 (PD-1), exercise with isotype, no exercise with anti-PD-1 and no exercise with isotype. Treadmill-running was performed for 20 min/day, 4 days/week at a speed of 12 metres/minute. Resistance training consisted of hanging upside down on a wire-mesh screen for 1 min 2 days/week. Flow cytometry was used to measure TME immune populations. Tumour and liver samples were harvested, paraffin wax-embedded/sectioned and analysed using SlideViewer 2.9.0™. A total of 22 healthy volunteers underwent a single bout of high-intensity interval cycling. Blood was collected pre- and post-exercise. Flow cytometry was used to measure leucocyte subpopulations. MSTO-211H (mesothelioma) and PANC-1 (pancreatic cancer) cells were cultured with pre- and post-exercise serum, with/without HSV1716, and viability determined using alamarBlue^®. PANC-1 apoptosis and migration were assessed using caspase-3/7 and scratch assays, respectively. Results: In an orthotopic pancreatic cancer mouse model, combining exercise with immunotherapy significantly increased tumour necrosis and reduced metastatic potential. In both pancreatic cancer and mesothelioma models, this combination remodelled the tumour microenvironment, enhancing cytotoxic CD8⁺ T cell infiltration, upregulating Programmed Cell Death Protein 1 (PD-1), and reducing Myeloid-Derived Suppressor Cells and regulatory T cells (Tregs). Complementary human studies revealed an acute systemic release of Natural Killer cells and a reduction in Tregs following high-intensity interval exercise in healthy volunteers. Moreover, exercise-conditioned serum from these participants exerted anti-cancer effects on pancreatic cancer and mesothelioma cell lines. Conclusions: Altogether, these findings highlight exercise as a promising adjunct to immunotherapy for poorly immunogenic cancers such as pancreatic cancer and mesothelioma. Full article

Introduction and Background: High-grade serous ovarian carcinoma (HGSOC) is notorious for its poor prognosis owing to its inherent biological aggressiveness and development of chemoresistance. The mechanistic target of rapamycin (mTOR) pathway is dysregulated in 55% of epithelial ovarian cancers, representing an appealing therapeutic target. To date, the clinical trials of mTOR inhibitors have shown modest response. In this study, we investigated the mTOR pathway in a clinical cohort of primary, chemo-naive, high-grade ovarian cancer samples, along with its regulatory post-transcriptional miRNA regulation. Methodology: We performed differential gene expression analysis on 100 HGSOC patients from TCGA and 80 healthy controls (i.e., normal ovarian tissue) from GTEx. The differentially expressed genes (DEGs) were overlaid onto the KEGG mTOR signalling pathway, followed by functional enrichment analysis. Next, we conducted differential miRNA expression analysis on the same cohort and identified regulatory miRNA–mTOR gene pairs involved in cancer pathogenesis. Finally, we constructed an interaction network and identified key hub genes and miRNAs with potential prognostic significance. Results: We identified 95 mTOR pathway genes that were significantly differentially expressed, involving upstream regulators, core components, and downstream effectors. Functional pathway analysis revealed a prominent shift toward mTORC1 activation, accompanied by paradoxical activation of autophagy. The let-7 miRNA family was identified as a key regulator of the mTOR pathway, potentially facilitating disease progression. RICTOR downregulation, a key component of the mTORC2 complex, appears to play a critical role in this histotype. In addition, FNIP1, a tumour suppressor gene implicated in mTOR dysregulation, was found to correlate with survival outcomes. Conclusions: We propose a model of dual activation of mTORC1 and autophagy in HGSOC as the metabolic rewiring enabling cancer progression under nutrient and cellular stress. Full article

Transcriptional regulation is pivotal for developmental processes and cell fate specification in homeostasis. One particularly relevant group of transcription factors is the sine oculis homeobox (SIX) family, which is involved in a wide range of molecular processes from development to tissue maintenance. Within this family, distinct subfamilies exhibit specific DNA-binding preferences and can function as transcriptional activators or repressors. In this review, we focus on the Optix/SIX3–SIX6 subfamily and discuss their roles as transcriptional regulators, as well as the consequences of their deregulation for neuronal and ocular development and for the maintenance of tissue homeostasis. We further examine how SIX3 can act either as a tumour suppressor or as a marker of poor prognosis in different cancer types. Moreover, we summarize recent findings on the role of SIX3 in pancreatic β cells and highlight emerging evidence that SIX2 also contributes to β-cell identity and regulatory stability. Downregulation of SIX2 and SIX3 alters gene regulatory programs associated with β-cell homeostasis and contributes to type 2 diabetes. As accumulating evidence links members of the SIX family to cancer and metabolic disease, it is crucial to characterize how these transcription factors regulate cell identity, with important implications for disease mechanisms and therapeutic strategies. Full article

Early identification of the risk of malignant transformation in oral potentially malignant disorders (OPMDs) is critical for improving outcomes in oral squamous cell carcinoma (OSCC). This comprehensive review examines immunological biomarkers obtained from minimally invasive oral cytobrush (OCB) specimens for the early detection of OSCC within a precision medicine framework. The objectives were to (1) identify and characterise key immunological biomarkers associated with early oral carcinogenesis; (2) evaluate the diagnostic utility of OCB sampling for detecting these biomarkers; and (3) explore the potential of OCB-based profiling to support personalised screening and patient management. The review highlights the potential advantages of OCB compared with conventional diagnostic methods, as reported in the literature, particularly its ability to capture early malignant changes through immunological analysis. Evidence is discussed for biomarker pathways related to cell-cycle and differentiation dysregulation (p53, Ki-67, CKs), inflammation-driven epithelial transformation (IL-1β, IL-6, IL-8, TNF-α), and immune suppression and checkpoint activation (PD-L1, B7-H6). OCB provides reliable and patient-friendly cyto-salivary samples that are suitable for immunological and molecular analyses. Aberrant biomarker expression detected in OCB specimens correlates with epithelial dysplasia and reflects early non-invasive neoplastic transformation, supporting the diagnostic value of integrated biomarker panels. Overall, OCB-based immunoanalysis represents a practical, non-invasive approach for the early detection of OSCC. Emerging technologies, including AI and multi-omics approaches, may further support the precision and predictive values of immunological analysis for OSCC. When combined with relevant biomarker pathways reflecting tumour biology and host immune responses, this strategy could offer a strong foundation for precision-medicine screening. It may also support personalised monitoring in patients with OPMDs. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most hard to treat malignancies, characterised by significant immune evasion and resistance to current systemic agents. Despite substantial progress in understanding tumour immunology across other cancer types, PDAC continues to exemplify an immunologically “cold” tumour, where a desmoplastic stroma, inadequate T-cell infiltration, and complex immunosuppressive networks combine to impede effective anti-cancer immunity. This review summarises current knowledge on the mechanisms underlying immune escape in PDAC, including aberrant antigen presentation, stromal–immune crosstalk, recruitment of regulatory T cells and myeloid-derived suppressor cells, and the metabolic and hypoxic constraints imposed by the tumour microenvironment. We also discuss recent advances in preclinical and clinical studies aiming to overcome these barriers, ranging from stromal modulation and targeting immune checkpoints to integrating radiotherapy, chemotherapy, and DNA damage response modulation to enhance immunogenicity. Special emphasis is placed on the emerging concept of therapeutic replication stress and its potential to induce immunogenic cell death and reshape the tumour immune landscape. We outline the mechanistic basis for treatment resistance of PDAC and discuss strategies to convert the malignancy from an immune-resistant to an immune-responsive state. Full article

The escalating incidence of colorectal cancer (CRC), particularly the alarming rise in early-onset cases, necessitates a paradigm shift from a purely genetic perspective to a broader investigation of promising pathways. This review explores the “nutri-epigenetic” interface, positioning liquid biopsy as a critical technology for translating dietary impacts into actionable clinical biomarkers. We contrast the molecular consequences of the Western dietary pattern, characterized by methyl-donor deficiency and pro-inflammatory metabolites, with the protective mechanisms of the Mediterranean diet. Mechanistically, we detail how Western-style diets drive a specific “epigenetic double-hit”: promoting global DNA hypomethylation (destabilizing LINE-1) while paradoxically inducing promoter hypermethylation of critical tumour suppressors (MLH1, APC, MGMT) and silencing tumour-suppressive microRNAs (miR-34b/c, miR-137) via methylation of their encoding genes. Conversely, we highlight the capacity of Mediterranean bioactive compounds (e.g., resveratrol, curcumin, butyrate) to inhibit DNA methyltransferases and restore epigenetic homeostasis. Bridging molecular biology and clinical utility, we demonstrate how these diet-sensitive signatures, specifically circulating methylated DNA and dysregulated microRNAs, can be captured via liquid biopsy. We propose that these circulating analytes serve as dynamic, accessible biomarkers for monitoring the molecular progression toward a carcinogenic state, thereby establishing a novel framework for personalized risk stratification and validating the efficacy of preventive nutritional strategies. Full article

Familial cancers are caused by inherited mutations in specific genes that regulate cell growth, division, and repair. Approximately 5–10% of all cancer cases have a hereditary component, where germline mutations in certain genes increase an individual’s susceptibility to developing cancer. Two major categories of genes are involved in cancer development: tumour suppressor genes and oncogenes. Both play critical roles in regulating normal cell behaviour, and when mutated, they can contribute to uncontrolled cell proliferation and tumour formation. In addition to genetic mutations, epigenetic alterations also play a significant role in familial cancer. Epigenetics refers to changes in gene expression due to DNA methylation, histone modifications, and the dysregulation of non-coding RNAs without alter the underlying DNA sequence. Familial cancer syndromes follow various inheritance patterns, including autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance, each with distinct characteristics. Identifying genetic mutations associated with familial cancers is a cornerstone of genetic counselling, which helps individuals and families navigate the complex intersection of genetics, cancer risk, and prevention. Early identification of mutations enables personalized strategies for risk reduction, early detection, and, when applicable, targeted treatment options, ultimately improving patient outcomes. Full article

Human zinc finger Ran-binding protein 3 (ZRANB3) is crucial for DNA damage tolerance (DDT), as it prevents excessive damage, restores fork progression, and ultimately maintains genome stability. This unique and ancient architecture mainly exerts its function during replication fork reversal (RFR) and within the p53/Polι axis; thus, ZRANB3 is considered a tumour suppressor. However, possible additional roles in DNA synthesis and cell metabolism have been proposed. In tumour cells, ZRANB3 gene expression is deregulated, a condition that is frequently associated with poor survival and adverse clinical outcomes. ZRANB3 can be altered by functional mutations, gene copy number alterations, and a combination of the two. Although its mRNA levels typically correlate with p53 expression, this correlation breaks down in the context of p53 mutations and high proliferative activity. This comprehensive review integrates the currently available yet fragmented literature on ZRANB3, both at the gene and protein levels, examines its regulation in cancer development, and discusses the evidence supporting its role as a tumour suppressor and prognostic biomarker. Full article

Background: Suppressor of Cytokine Signalling 6 (SOCS6) is a cytokine signalling suppressor that regulates receptor tyrosine kinase pathways by promoting degradation of signalling proteins, thereby controlling cell growth and survival. One of these tyrosine kinase receptors, Erythropoietin Receptor (EPOR), plays a critical role in CRC progression by enhancing tumour metabolism, angiogenesis, proliferation, and growth. This study investigates the molecular mechanisms governing SOCS6’s role in CRC pathogenesis using in vitro cell models and examines its interaction with EPOR expression following gene knockdown. Methods: Bioinformatics interaction between SOCS6 and EPOR were investigated using molecular visualization. HT-29 and COLO 320DM colorectal cancer cells were transfected with SOCS6 siRNA followed by measurement of SOCS6 and EPOR expression levels by qRT-PCR. The selected knockdown concentration was used in functional assays assessing cell viability, colony formation, migration, apoptosis, and invasion. Results: Bioinformatic results showed interaction between SOCS6 and EPOR through polar bonds. Furthermore, SOCS6 silencing increased cell viability and colony formation in both cell lines and significantly enhanced migration in COLO 320DM cells. Active caspase-3 levels were elevated markedly in HT-29 cells post SOCS6 knockdown, consistent with caspase-3’s reported oncogenic role in CRC. Moreover, EPOR knockdown selectively altered SOCS6 expression in HT-29 cells, indicating a regulatory feedback loop. EPOR silencing elevated cell viability at 24 h in both cell lines but caused a significant decrease in COLO 320DM cells at 72 h. Conclusions: These findings identify the SOCS6–EPOR axis as a potential target for personalized CRC therapy, supporting SOCS6’s tumour-suppressive and diagnostic roles. Full article

Fine particulate matter (PM2.5) is a major air pollutant linked to lung cancer progression. In Southeast Asia, seasonal smoke-haze produces biomass-derived PM2.5, yet its acute effects on genetically diverse lung tumours remain unclear. We investigate how Chiang Mai haze-derived PM2.5 impacts oxidative stress and gene expression in three non-small-cell lung cancer (NSCLC) cell lines: A549 (KRAS-mutant), NCI-H1975 (EGFR-mutant), and NCI-H460 (KRAS/PIK3CA-mutant). Cells were exposed to PM2.5 (0–200 µg/mL) and assessed for viability (MTT), reactive oxygen species (ROS; H₂O₂, •OH) and malondialdehyde (MDA) levels, mitochondrial-associated fluorescence, and whole-transcriptome responses. Acute exposure caused dose- and time-dependent viability loss, with A549 and NCI-H1975 more sensitive than NCI-H460. ROS profiling normalized to viable cells revealed genotype-specific oxidative patterns: cumulative increases in A549, sharp reversible spikes in NCI-H1975, and modest changes in NCI-H460. MitoTracker intensity trended downward without significance, with subtle fluorescence changes and particulate uptake. RNA-seq identified robust induction of xenobiotic metabolism (CYP1A1, CYP1B1), oxidative/metabolic stress mediators (GDF15, TIPARP), and tumour-associated genes (FOSB, VGF), alongside repression of tumour suppressors (FAT1, LINC00472). Pathway enrichment analyses highlighted oxidative stress, IL-17, NF-κB, and immune checkpoint signaling. Together, biomass haze-derived PM2.5 from Northern Thailand drives genotype-dependent oxidative stress and transcriptional remodeling in NSCLC cells. Full article

Non-coding RNA (ncRNA) encompasses a large family of molecules that are crucial regulators of gene expression. This family includes microRNA, piwi-interacting RNA, and long non-coding RNA (lncRNA); each class is associated with different mechanisms of action that influence gene expression. Based on the available evidence, these molecules have important roles in physiological and pathological processes. For example, ncRNAs are strongly implicated in oncogenesis by mediating the expression of tumour suppressors and oncogenes. This review comprehensively describes the latest findings regarding the roles of lncRNAs in the pathophysiology of melanoma. Key aspects of melanoma biology and various mechanisms regulated by lncRNAs are discussed. Furthermore, future areas exploring potential biomarkers and therapeutic targets are presented. Full article

The tumour suppressor TP53 (tumor protein p53) is a master regulator of cell cycle, DNA repair, and apoptosis, and its mutation is a hallmark of cancer, with individual mutations exerting distinct effects on tumour biology. Despite accounting for ~7% of all TP53 variants, splice site mutations remain the least studied class, and their functional and clinical consequences are poorly understood. We analyzed 25,058 TP53 variants (18,562 somatic; 6496 germline) to characterize the frequency, molecular impact, transcriptional effects, genomic instability, and clinical outcomes of splice mutations. These alterations showed distinct distributions and substitution patterns between germline and somatic contexts and were frequently associated with copy number alterations, reduced TP53 mRNA, and variable protein expression. Transcriptomic profiling identified two transcriptional phenotypes: one with global suppression of canonical p53 target genes and another with mixed activation and repression independent of tumour type. Genomic instability was elevated in a subset of splice-mutant tumours, correlating with increased relapse risk, while other splice mutations showed lower instability but divergent clinical outcomes, including unexpectedly poor prognoses. Our findings fill a critical knowledge gap, defining the biological and clinical spectrum of TP53 splice site mutations and highlighting their potential as prognostic biomarkers and therapeutic targets in precision oncology. Full article

Proteoglycans (PGs) are highly glycosylated proteins of great importance both structurally and for signalling in the extracellular matrix (ECM) as well as cell surfaces. In breast cancer (BC), they control the structure of tissue architecture, cellular communication pathways and tumour–stroma interactions, thus affecting adhesion, migration, angiogenesis, immune evasion, and metastasis. Their structural heterogeneity supports either subtype- or context-dependent functions. This review combines current studies of PGs in BC according to their classification into intracellular, cell-surface, pericellular, extracellular, and small leucine-rich PGs and a range of non-classical PGs. A literature-driven approach to focus on molecular mechanisms and clinical correlations will demonstrate how PGs respond with collagens, growth factors, cytokines, and proteolytic enzymes in order to modulate the ECM and affect therapy resistance. Indeed, PGs including syndecans, glypicans, perlecan, versican, biglycan and decorin showed the potential to be promoters or suppressors of cancer, with local effects on invasion, and have a significant modulating effect on BC subtypes or the prognosis and therapeutic response and may potentially serve as new biomarkers for stratification and liquid biopsy candidates. Furthermore, PGs appear to modulate the tumour immune landscape, are involved in the development of metastatic niches, and underlie signalling pathways like Wnt or TGFβ in a subtype-dependent manner, extending their translational prospects and therapeutic utility. PGs, taken together, seem to be major modulators of BC, with particular relevance for precision medicine. Full article