Apoptosis and tumor suppression prevent cell proliferation in response to genomic damage. Polymorphisms in genes involved in these pathways can alter their function, facilitating the onset of cancer. Detecting these polymorphisms would assess the individual risk of developing different types of cancer. Therefore, the main goal of this study is to analyze the association between a set of genetic polymorphisms involved in apoptosis and tumor suppression and the risk of developing prostate cancer (PCa) in a population from Galicia. Accordingly, we performed a case-control study with 291 patients diagnosed with PCa and 249 healthy controls. A total of 19 genetic polymorphisms located in loci BCL2, CASP9, CASP8, CASP7, FAS, FASLG, BIRC5, TP53, MDM2, and MDM4 were genotyped. Their association with PCa was approached from a global perspective and stratified by the body mass index (BMI). Globally, a statistically significant association with PCa was found for polymorphisms rs1052576 (CASP9) and rs990431 (BIRC5), with carriers of the G allele (ORGA/AA = 2.14; p = 0.002) or the CC genotype (ORCC/CG = 1.92; p = 0.037), respectively, manifesting greater susceptibility to the disease. The analyses stratified by BMI yielded statistically significant results for polymorphisms rs1052576 (CASP9), rs3740286 (FAS), rs9904341 (BIRC5), rs2279744 (MDM2), rs937283 (MDM2), and rs1380576 (MDM4), with odds ratios between 2.47 and 8.00 in overweight or obese participants. These results indicate the differential effect of allelic variants of six SNPs on prostate cancer risk in patients with overweight or obesity. Further studies in larger cohorts should be conducted to confirm these findings.

Circular RNAs (circRNAs) are covalently closed, single-stranded RNAs generated via backsplicing. They are highly stable and evolutionarily conserved, making them promising candidates for cancer therapy and diagnosis. CircRNAs regulate cancer progression by modulating genome instability, angiogenesis, metastasis, stemness, and chemoresistance. They do so through mechanisms including microRNA (miRNA) sponging, protein interaction, translational templating, and transcription/translation regulation. CircRNAs play a critical role in cancer immunotherapy. They modulate immune checkpoint blockade (ICB) responses and cytokine secretion to reshape the tumor immune microenvironment (TME). CircRNAs also serve as stable platforms for neoantigen-based cancer vaccines and improve in vivo chimeric antigen receptor T cell (CAR-T) therapy by replacing unstable linear mRNA. Additionally, circRNAs are potential noninvasive biomarkers due to their abundance in body fluids and differential tumor-normal expression. Despite challenges such as unclear regulatory networks, off-target effects, and inefficient delivery, this review systematically summarizes the biogenesis of circRNAs, their functional mechanisms, their roles in cancer progression, and their applications in cancer immunotherapy. The review also highlights their utility as biomarkers and future translational directions, providing a focused overview of their potential to advance cancer immunotherapy.

The incidence of cancer increases markedly with aging, and the two processes share underlying molecular mechanisms. In the context of global population aging and rising cancer incidence, nine convergent hallmark axes have been identified: genomic instability, epigenetic drift, inflammation-immunity imbalance, microbiome dysbiosis, metabolic reprogramming, telomere attrition, stem cell exhaustion, cellular senescence, and autophagy dysfunction. These hallmarks constitute an integrated regulatory network that operates synergistically, antagonistically, or through bidirectional feedback across molecular, cellular, and microenvironmental levels. Genomic instability, epigenetic remodeling, chronic inflammation, microbiome dysbiosis, and metabolic reprogramming in aging often act synergistically to promote tumorigenesis, whereas telomere attrition and stem cell exhaustion primarily exert antagonistic, tumor-suppressive effects. Cellular senescence and autophagy dysfunction display context-dependent dual roles. Importantly, this network framework has direct relevance to cancer therapeutics. Although chemotherapy, radiotherapy, and immunotherapy effectively suppress tumor progression, they frequently induce therapy-induced senescence, characterized by cell-cycle arrest and a senescence-associated secretory phenotype, thereby accelerating functional decline and increasing long-term toxicities in older patients. The proposed "synergistic-antagonistic-dual" framework linking aging and cancer not only helps explain the disproportionate cancer burden in older adults but also supports a "one drug, two targets" therapeutic paradigm. Targeting these shared pathways has delayed aging phenotypes and suppressed tumorigenesis in preclinical studies and early clinical trials, highlighting the potential of integrated interventions that concurrently address aging and cancer.

Peto's paradox (Pp) results from the evidence that in mammals there is no obvious positive correlation between body size, lifespan, and cancer incidence. Posing the question of which mechanisms are responsible for this. Comparative studies searching for specific anticancer mechanisms as putative solutions to Pp have been undertaken in mammals. The result of these efforts are further inconsistencies leading to ad-hoc hypotheses and unnecessary complexity. In contrast to this, we present evidence that the cellular stress responses (CSRs), aimed at curtailing proteotoxic stress and assuring cell survival are necessary for enabling carcinogenesis. Yet, natural selection adjusts the performance of the CSRs according to the life history of each species and because of this, cancer is mostly delayed to the post-reproductive stage in all mammalian species, resulting in a limited impact of cancer on species fitness and viability. From this perspective, the need of evolving anticancer mechanisms, suggested by Pp is weakened or disappears and the paradox is likely resolved.

Emerging insights from immunometabolism underscore the importance of metabolic-immune interactions in shaping the brain tumor microenvironment and potentially influencing brain behavior and neurological outcomes. Although previous studies have suggested potential links between metabolites and risks of malignant brain tumor development, the causal relationship remains unclarified.

This study is aimed at distinguishing the phenotypes of low-grade gliomas based on the P53 signaling pathway gene set, revealing the transcriptomic changes in different phenotypes, screening phenotype-related feature genes, constructing a TP53 score, quantitatively describing TP53-related phenotypes, and predicting the response of glioma patients to chemotherapy.

N7-methylguanosine (m7G) is an important RNA modification involved in the regulation of gene expression during transcription. While its roles in mRNAs and tRNAs are increasingly understood, the distribution and function of m7G in long non-coding RNAs (lncRNAs), particularly in oral squamous cell carcinoma (OSCC), remain poorly understood. This study aimed to systematically characterize the m7G methylation landscape of lncRNAs in OSCC and investigate the oncogenic function and regulatory mechanism of the m7G-modified lncRNA DPY19L1P1.

Acute myeloid leukemia (AML) is an aggressive and molecularly diverse hematologic malignancy with unfavorable clinical outcomes and limited options for targeted therapy. This study investigated whether polypyrimidine tract-binding protein 1 (PTBP1), an RNA-binding protein (RBP), affects AML progression by binding to WNK lysine-deficient protein kinase 1 (WNK1).

Centromere protein A (CENPA) is a histone H3 variant essential for centromere function and has been implicated in tumorigenesis in several cancers. However, its clinical significance and biological role in endometrial cancer (EC) remain poorly characterized. This study aimed to elucidate the oncogenic function and underlying mechanisms of CENPA in EC progression.

Collagen type XI alpha 1 (COL11A1) is overexpressed in pancreatic cancer and is often associated with poor survival, chemoresistance, and tumor recurrence. However, the role of COL11A1 in pancreatic cancer remains poorly understood.

Gastric cancer (GC) is among the most frequently diagnosed malignancies worldwide. Identifying novel therapeutic targets is of great significance.

Thyroid collision tumors (TCTs) are rare thyroid malignancies characterized by the coexistence of distinct tumor types. We investigated the histopathology, immunohistochemistry, and gene mutations to comprehensively characterize the heterogeneity of TCTs.

DNA methylation is a key epigenetic modification catalyzed by DNA methyltransferases (DNMTs) and predominantly occurs at cytosine-phosphate-guanine (CpG) islands, which are often located in gene promoter regions. Hypermethylation of CpG islands within gene promoters can silence tumor suppressor gene expression, thereby disrupting normal cellular functions, including maintenance of genomic stability and regulation of cell growth, and contributing to tumor initiation and progression. In contrast, global hypomethylation may promote genomic instability and oncogene activation. This review discusses the molecular mechanisms underlying DNA methylation and evaluates its functional and clinical significance in colorectal and gastric cancers, with emphasis on its potential application as a noninvasive biomarker for diagnosis.

Neuroblastoma (NB) is the most common extracranial solid tumor among pediatric cancers and accounts for approximately 15% of childhood cancer-related deaths. Neurotrophic receptor tyrosine kinases (NTRKs) are genes that play critical roles in the development and function of the nervous system. Therefore, elucidating the role of NTRKs in NB is important for both understanding basic biological mechanisms and developing novel therapeutic approaches. Specifically, NTRK fusions are being investigated as potential biomarkers and therapeutic targets for targeted therapy strategies. The tumor-agnostic TRK inhibitors larotrectinib and entrectinib are used to treat advanced or metastatic solid tumors with NTRK gene fusions. Accordingly, this study aimed to investigate the clinical significance of NTRK1, NTRK2, and NTRK3 point mutations, gene fusions, and protein expression, and to assess the effectiveness of these in guiding targeted therapy decisions in NB.

Single-stranded DNA gaps (ssDNA gaps) have emerged as a potential indicator of therapeutic response in cancer. Accumulation of ssDNA gaps is associated with increased sensitivity of cancer cells to genotoxic therapies like PARP inhibitors (PARPi) and cisplatin chemotherapy. However, efficient repair or suppression of ssDNA gap formation is associated with therapy resistance and treatment failure. Therefore, understanding how ssDNA gaps form and are repaired can help identify biomarkers that can guide new treatment strategies to overcome resistance. In this review, we discuss different sources of ssDNA gap formation and the repair mechanisms that have been characterized to date. We bring together current knowledge on how these gaps are processed and what their ultimate fate may be. Finally, we discuss how established drugs like PARPi, hydroxyurea, and platinum compounds, induce and/or exploit ssDNA gaps. Throughout this review, we highlight ssDNA gaps as a potential therapeutic vulnerability that can be used to advance personalized cancer therapy.

The recommended first-line therapy for BRAF V600E mutant non-small cell lung cancer (NSCLC) is a combination of dabrafenib and trametinib. Most patients respond to the initial therapy, but some show resistance in the early stages. Additionally, immune checkpoint inhibitors (ICIs) are often used after resistance develops; however, the benefits of ICIs in patients with BRAF V600E mutant NSCLC remain unclear.

Objective. Multiple endocrine neoplasia type 1 (MEN1) is a very rare genetic disorder characterized by an autosomal dominant inheritance. We aim through this case series to delineate the wide spectrum of its clinical features. Methods. In the present study, we report the clinical and genetic findings of four siblings affected by this disorder. DNA was extracted from patients' blood leukocytes using a phenol-chloroform method and assessed for purity with a NanoDrop spectrophotometer. Ten exons of the MEN1 gene were amplified by PCR, verified by gel electrophoresis, and sequenced using Big Dye Terminator chemistry followed by capillary electrophoresis. The sequences were than analyzed with CHROMAS and compared to reference sequences. As for the variant, interpretation and pathogenicity were assessed using Ensembl, ClinVar, dbSNP, gnomAD, Alamut Visual, and VARSOME. Results. We highlight the wide range of phenotypes encompassing primary hyperparathyroidism, macroprolactinoma, lipomas, papillary thyroid carcinoma, ectopic thyroid, multinodular goiter, and bilateral adrenal nodules observed in this family contrasting with the same pathogenic frameshift mutation. We also pinpoint to a second mutation detected in two of the siblings while discussing its pathogenicity. Finally, we provide an overview of the clinical manifestations of MEN1 and its genetic background. Conclusion. This research sets the stage to further investigate the molecular mechanisms underlying the novel nonsense mutation. Additionally, it incites other research to explore the frequency of this mutation in other populations and finally to conduct functional studies.

Objective. The BAG cochaperone 1 (BAG1) binds to oncogene BCL2 and markedly enhances its anti-apoptotic effects. This cochaperone represents a link between growth factor receptors and anti-apoptotic mechanisms mediated by endoplasmic reticulum stress. BAG1 interacts with the glucocorticoid receptor and modulates its transcription activity. As a cochaperone for several HSP70 proteins, it participates in control of protein folding. The present study aims to investigate the regulation of the BAG1 mRNA expression in U87MG glioblastoma cells by hypoxia and glucose or glutamine deprivation, depending on the inhibition of ERN1 (endoplasmic reticulum to nucleus signaling 1) with the intent to reveal the role of ERN1 signaling in the regulation of this gene expression and function in oncogenesis. Methods. The U87MG glioblastoma cells (transfected by an empty vector; control) and cells with inhibited ERN1 endoribonuclease and protein kinase (dnERN1) or only ERN1 endoribonuclease (dnrERN1) were used. Silencing of ERN1 and XBP1 mRNAs for suppression of ERN1 function was also used. A hypoxic condition was created by dimethyloxalylglycine (4 h). DMEM medium without glucose or glutamine was used for glucose and glutamine deprivation (16 h). The expression level of the BAG1 mRNA was studied by real-time qPCR and normalized to the beta-actin mRNA. Results. Inhibition of the endoribonuclease activity of ERN1 significantly decreased BAG1 mRNA expression. However, a lesser suppression of this mRNA expression was observed in dnERN1 cells (with inhibited ERN1 endoribonuclease and protein kinase) indicating the involvement of protein kinase in controlling BAG1 expression. The silencing of ERN1 and XBP1 mRNAs also reduced the expression of BAG1 mRNA demonstrating the involvement of XBP1s in this regulation. The expression of the BAG1 gene was resistant to glutamine deprivation and upregulated in response to glucose deprivation in control glioblastoma cells. However, the inhibition of ERN1 increased the sensitivity of BAG1 gene expression to both glucose and glutamine deprivation. Furthermore, the expression of the BAG1 gene was increased under hypoxia in control U87MG cells; however, a greater induction was observed in dnERN1 cells. Conclusion. The results of this study demonstrated that ERN1 inhibition reduces BAG1 mRNA expression through the endoribonuclease activity of ERN1 and that protein kinase activity counteracts endoribonuclease in regulating the expression of BAG1 mRNA. Moreover, ERN1 inhibition also enhances the sensitivity of BAG1 mRNA expression to nutrient supply and hypoxia resulting in reduced resistance of glioblastoma cells.

Objective. Phosphoenolpyruvate carboxykinase (PCK) catalyzes the conversion of oxaloacetate to phosphoenolpyruvate and regulates pyruvate metabolism and gluconeogenesis in response to glucocorticoid and insulin stimuli. Mitochondrial isoform of this enzyme (PCK2) is overexpressed in glioblastoma cells and participates in metabolic reprogramming and cell proliferation. This study aims to examine the impact of ERN1 (endoplasmic reticulum to nucleus signaling 1) inhibition on PCK2 expression and sensitivity to glucose and glutamine deprivation to determine the role of ERN1 signaling in the regulating its expression in glioblastoma cells. Methods. The glioblastoma cell line U87MG and two genetically modified variants of these cells were used. These were glioblastoma cell sublines with suppressed endoribonuclease and protein kinase activities of ERN1 (dnERN1) or only ERN1 endoribonuclease (dnrERN1), and control cells transfected with an empty vector. The suppression of ERN1 function by silencing of ERN1 and XBP1 mRNAs was also used. Hypoxia was generated using the HIF1A prolyl hydroxylase inhibitor dimethyloxalylglycine. For glucose and glutamine deprivation, DMEM medium without glucose or glutamine was used. The expression level of the PCK2 mRNA was analyzed by real-time qPCR and normalized to the beta-actin mRNA. Results. It has been demonstrated that PCK2 mRNA expression is significantly decreased in dnERN1 glioblastoma cells. Similar suppression of this mRNA expression was also observed in cells with only the endoribonuclease activity of ERN1 inhibited, indicating that this enzymatic activity is involved in the regulation of PCK2 expression. The silencing of ERN1 and XBP1 mRNAs also induced similar changes in PCK2 mRNA expression, possibly mediated by XBP1s. The expression of PCK2 was enhanced under glutamine deprivation in control glioblastoma cells, but inhibition of ERN1 activity strongly increased this effect. Upregulated PCK2 expression was also observed in control glioblastoma cells under glucose deprivation. However, the inhibition of ERN1 activity strongly increased the sensitivity of this gene expression to glucose deprivation. Furthermore, PCK2 mRNA expression was resistant to hypoxic conditions in cells with native ERN1. At the same time, in glioblastoma cells with inhibited ERN1 activity, a strong induction of PCK2 expression was observed. Conclusion. The results of this study demonstrated that ERN1 inhibition reduces PCK2 mRNA expression through the ERN1 endoribonuclease activity. This mRNA expression is upregulated under glutamine and glucose deprivation. Moreover, ERN1 inhibition strongly enhanced the sensitivity of PCK2 mRNA expression to glucose and glutamine deprivation as well as to hypoxia.

Mixed-phenotype acute leukemias (MPALs) are a rare and aggressive group of leukemias, accounting for approximately 2%-5% of all leukemia cases. MPAL is characterized by the expression of markers from more than one hematopoietic lineage, either myeloid and lymphoid, which can be identified through flow cytometry immunophenotyping. This study aims to describe the clinicopathological, immunophenotypic, and cytogenetic features of a cohort of 27 patients diagnosed with MPAL at our institution.