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The present review demonstrates the major tumor suppressor genes, including TP53, CDKN2A and SMAD4, associated with pancreatic cancer. Each genes role, prevalence and impact on tumor development and progression are analyzed, focusing on the intricate molecular landscape of pancreatic cancer. In addition, this review underscores the prognostic significance of specific mutations, such as loss of TP53, and explores some potential targeted therapies tailored to these molecular signatures. The findings highlight the importance of genomic analyses for risk assessment, early detection and the design of personalized treatment approaches in pancreatic cancer. Overall, this review provides a comprehensive analysis of the molecular intricacies of pancreatic tumors, paving the way for more effective and tailored therapeutic interventions.

Background: Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a rare cause of Cushing's syndrome due to bilateral adrenocortical macronodules. Germline inactivating variants of the tumor suppressor gene ARMC5 are responsible for 20–25% of apparently sporadic PBMAH cases and 80% of familial presentations. ARMC5 screening is now routinely performed for PBMAH patients and families. Based on literature review and own observation, this study aims to give an overview of both published and unpublished ARMC5 genetic alterations and to compile the available evidence to discriminate pathogenic from benign variants. Results: 146 different germline variants (110 previously published and 36 novel) are identified, including 46% missense substitutions, 45% truncating variants, 3% affecting splice sites, 4% in-frame variants and 2% large deletions. In addition to the germline events, somatic 16p loss-of-heterozygosity and 104 different somatic events are described. The pathogenicity of ARMC5 variants is established on the basis of their frequency in the general population, in silico predictions, familial segregation and tumor DNA sequencing. Conclusions: This is the first extensive review of ARMC5 pathogenic variants. It shows that they are spread on the whole coding sequence. This is a valuable resource for genetic investigations of PBMAH and will help the interpretation of new missense substitutions that are continuously identified. [ABSTRACT FROM AUTHOR]

Oncogenes are typically overexpressed in tumor tissues and often linked to poor prognosis. However, recent advancements in bioinformatics have revealed that many highly expressed genes in tumors are associated with better patient outcomes. These genes, which act as tumor suppressors, are referred to as "paradoxical genes." Analyzing The Cancer Genome Atlas (TCGA) confirmed the widespread presence of paradoxical genes, and KEGG analysis revealed their role in regulating tumor metabolism. Mechanistically, discrepancies between gene and protein expression-affected by pre- and post-transcriptional modifications-may drive this phenomenon. Mechanisms like upstream open reading frames and alternative splicing contribute to these inconsistencies. Many paradoxical genes modulate the tumor immune microenvironment, exerting tumor-suppressive effects. Further analysis shows that the stage- and tumor-specific expression of these genes, along with their environmental sensitivity, influence their dual roles in various signaling pathways. These findings highlight the importance of paradoxical genes in resisting tumor progression and maintaining cellular homeostasis, offering new avenues for targeted cancer therapy. Typically, oncogenes show higher expression in tumors and are linked to poor prognoses. However, some highly expressed genes in tumors are associated with better outcomes and act as tumor suppressors, termed paradoxical genes. We explored these genes using bioinformatics, revealing their significant roles in regulating tumor metabolism and immune microenvironments, offering new insights for targeted cancer therapy. Created in BioRender. ZHAO, X. (2025) https://BioRender.com/b00e214. [ABSTRACT FROM AUTHOR]

Microproteins, historically overlooked, are emerging as key players in cancer biology. Advances in genomics and proteomics enable systematic identification of cancer-associated microproteins. Microproteins contribute to cancer pathogenesis, are an important source of cryptic cancer antigens, and may offer novel therapeutic targets. Harnessing the potential of microproteins could revolutionize cancer diagnostics, therapeutics, and immunotherapy. Cancer continues to be a major global health challenge, accounting for 10 million deaths annually worldwide. Since the inception of genome-wide cancer sequencing studies 20 years ago, a core set of ~700 oncogenes and tumor suppressor genes has become the basis for cancer research. However, this research has been based largely on an understanding that the human genome encodes ~19 500 protein-coding genes. Complementing this genomic landscape, recent advances have described numerous microproteins which are now poised to redefine our understanding of oncogenic processes and open new avenues for therapeutic intervention. This review explores the emerging evidence for microprotein involvement in cancer mechanisms and discusses potential therapeutic applications, with an emphasis on highlighting recent advances in the field. [ABSTRACT FROM AUTHOR]

Parathyroid carcinoma (PC) and atypical parathyroid tumors (APT) are incompletely understood and pose challenges in definitive diagnosis. FLCN sequence variants have recently been linked to PC and APT. Inactivating mutations in the ubiquitously expressed FLCN tumor suppressor gene, encoding folliculin, cause Birt-Hogg-Dubé syndrome (BHD), a rare tumor predisposition syndrome. Germline inactivating FLCN variants, accompanied by somatic allelic loss, were reported in 2 unrelated patents with PC, both with clinical features, but no diagnosis, of BHD. Somatic frameshift variants of likely pathogenicity were reported in 1 patient with PC and 1 with APT. On the other hand, neither PC nor APT has been reported in sizeable BHD series. To better understand the frequency of FLCN variants in PC and APT, we analyzed a series of 10 patients with sporadic PC and 14 with APT by direct Sanger DNA sequencing. We identified no inactivating FLCN mutations in any of the PC or APT samples examined. A germline missense variant (p.Gly325Val), predicted as benign/tolerated, was seen in 1 PC and a synonymous variant in 1 APT. The absence of pathogenic mutations detected in our series of PC and APT further suggests that FLCN variants are rare in these tumors. Nevertheless, the potential roles of FLCN in the pathogenesis of PC and APT merits further consideration and study. [ABSTRACT FROM AUTHOR]

Despite the ongoing epidemic of youth vaping, the long-term health consequences of electronic cigarette use are largely unknown. We report the effects of vaping versus smoking on the oral cell methylome of healthy young vapers and smokers relative to nonusers. Whereas vapers and smokers differ in the number of differentially methylated regions (DMRs) (831 vs. 2,863), they share striking similarities in the distribution and patterns of DNA methylation, chromatin states, transcription factor binding motifs, and pathways. There is substantial overlap in DMR-associated genes between vapers and smokers, with the shared subset of genes enriched for transcriptional regulation, signaling, tobacco use disorders, and cancer-related pathways. Of significance is the identification of a common hypermethylated DMR at the promoter of HIC1 (hypermethylated in cancer 1), a tumor suppressor gene frequently silenced in smoking-related cancers. Our data support a potential link between epigenomic dysregulation in youth vapers and disease risk. These novel findings have significant implications for public health and tobacco product regulation. [ABSTRACT FROM AUTHOR]

Myelomatous bone disease is a complication characterized by lytic bone lesions, reduced bone formation, bone pain, and increased fracture risk. Understanding these underlying mechanisms is crucial for developing effective therapeutic approaches. Here we show the role of enhancer of zeste homolog 2 (EZH2) in bone lesions induced by myeloma cells. Our research reveals that cytokines produced by myeloma-associated adipocytes activate the expression of EZH2 in myeloma cells. Furthermore, we find that EZH2 forms a transcriptional repression complex with transcription factor AP2α. This complex promotes trimethylation at lysine 27 of histone H3 (H3K27me3) in the promoter region of the tumor suppressor gene EMP1, resulting in transcriptional silencing. EMP1 silencing leads to increased myeloma cell proliferation and the concomitant secretion of osteolytic cytokines that contribute to bone destruction. Importantly, EZH2 inhibitors effectively treat myeloma-induced osteolytic lesions. Thus, targeting EZH2 represents a potential therapeutic strategy for preventing and managing myeloma bone disease. Osteolytic bone disease is a complication that affects 80% of patients with multiple myeloma. Here, authors show that inhibition of EMP1 due to EZH2 activation results in increased proliferation of myeloma cells and up-regulation of osteoclastogenic cytokines that promote bone lesions. [ABSTRACT FROM AUTHOR]

Objective: Lung cancer is one of the main causes of cancer-related mortality globally, and it poses considerable therapeutic challenges. Polo-like kinase 1 (PLK1) exhibits upregulation in lung cancer, and PLK1 silencing promotes autophagy in lung cancer cells, which inhibits tumor progression. The phosphatase and tensin homolog deleted on chromosome ten (PTEN) acts as a tumor suppressor gene. This study aimed to investigate whether PTEN regulates autophagy and inhibits lung cancer-cell proliferation by suppressing PLK1. Material and Methods: In this study, we evaluated cell proliferation by silencing or overexpressing PLK1 and PTEN in A549 cells through 5-ethynyl-2'-deoxyuridine labeling and cloning experiments. The autophagy levels were detected through transmission electron microscopy, real-time quantitative polymerase chain reaction, and Western blot. Finally, the results of in vitro experiment were further verified using an in vivo xenograft tumor animal model. Results: The upregulation of PTEN suppressed PLK1 expression in lung cancer cells and reduced their proliferation rate. In addition, the overexpression of PTEN has been associated with the growth of lung cancer tumors. In parallel, the levels of autophagy of lung cancer cells rose in response to PTEN upregulation in vivo and in vitro. Conclusion: This study revealed that PTEN promotes the autophagy of lung cancer cells and inhibits cell proliferation and tumor growth by suppressing PLK1 expression. This finding provides a new strategy for lung cancer treatment by utilizing the autophagy-regulating effect of PTEN to inhibit lung cancer growth by targeting PLK1. [ABSTRACT FROM AUTHOR]

Background: Regeneration is the preferred approach to restore the structure and function after tissue damage. Rapid proliferation of cells over the site of damage is integral to the process of regeneration. However, even subtle mutations in proliferating cells may cause detrimental effects by eliciting abnormal differentiation. Interestingly deer antlers, arguably the fastest regenerating mammalian tissue, have not been reported, thus far, to grow malignant tumors. They provide a mammalian model to understand the possible mechanism by which rapid regeneration is achieved while avoiding the development of malignancies. Antler regeneration is based on the proliferation and differentiation of antler stem cells (AnSCs). Results: We identified 39 hub genes which may function in regulating the balance between rapid proliferation and genomic stability in the AnSCs during antler regeneration. Among these 39 genes, the tumor suppressor gene, BRCA1, was found to be more sensitive to DNA damage in the AnSCs compared to that in the deer somatic cells, and BRCA1 deletion in the AnSCs via CRISPR/Cas9 resulted in significantly higher levels of DNA damage. Lack of BRCA1 promoted cell apoptosis and cell senescence and inhibited cell proliferation and cell self-renewal. RNA-seq results showed that in the absence of BRCA1, the p53 signaling pathway was significantly up-regulated. Associated with this change, the cell apoptosis and cell senescence-relevant-genes, CDKN1A, CDKN2A and Fas were over expressed, but the expression of cell-cycle-progression-related genes was inhibited. In addition, BRCA1 expression levels were found to be more sensitive to endoplasmic reticulum stress (ERS) in the AnSCs compared to the somatic cells. Deletion of BRCA1 gene aggravated ERS and ERS-induced cell apoptosis. Conclusions: Our results revealed that BRCA1 is involved in sustaining rapid antler growth possibly via promotion of DNA damage repair that acts to maintain genome stability while protecting cells from p53/ERS-induced cell death. Understanding the mechanisms underlying the role played by BRCA1 in the process of antler regeneration is of great significance not only for regenerative medicine, but also for the understanding of cancer development. [ABSTRACT FROM AUTHOR]

Oncogenic gamma herpesviruses, including Epstein–Barr Virus (EBV) and Kaposi's Sarcoma-associated Herpesvirus (KSHV), are opportunistic cancer-causing viruses and induces oncogenesis through complex mechanisms, which involves manipulation of cellular physiology as well as epigenetic and epitranscriptomic reprogramming. In this review, we describe the intricate processes by which these viruses interact with the epigenetic machinery, leading to alterations in DNA methylation, histone modifications, and the involvement of non-coding RNAs. The key viral proteins such as EBNA1 and LMP1 encoded by EBV; LANA and vGPCR encoded by KSHV; play pivotal roles in these modifications by interacting with host factors, and dysregulating signaling pathways. The resultant reprogramming can lead to activation of oncogenes, silencing of tumor suppressor genes, and evasion of the immune response, which ultimately contributes to the oncogenic potential of these viruses. Furthermore, in this review, we explore current therapeutic strategies targeting these epigenetic alterations and discuss future directions for research and treatment. Through this comprehensive examination of the epigenetic and epitranscriptomic reprogramming mechanisms employed by oncogenic gamma herpesviruses, we aim to provide valuable insights into potential avenues for novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

The editorial in the journal "Frontiers in Toxicology" challenges current assumptions about mesothelioma as a genomic disease by reviewing disease pathogenesis and recent findings. It discusses the historical impact of asbestos exposure, the characteristics of asbestos fibers related to toxicity, and the mesothelial cell response to asbestos. The editorial also delves into the histopathology and molecular genetic characterization of pleural mesothelioma, highlighting the importance of genetic predisposition, epigenetic events, and the tumor microenvironment in disease progression. The research aims to distinguish the mechanism of asbestos action from the neoplastic progression of mesothelial cells, emphasizing the need for further studies on elongated mineral particles and genomic changes in asbestos-related diseases. [Extracted from the article]

Simple Summary: Oral cancer, a malignant neoplasm with invariable poor prognosis in the last 40 years (5-year survival rate of nearly 50%), accounts for a worldwide incidence of 377,713 new cases annually and 177,757 deaths per year. Oral cancer is usually preceded by oral potentially malignant disorders (OPMDs)—such as leukoplakia, oral lichen planus and oral submucous fibrosis—defined by the WHO Collaborating Centre for Oral Cancer as any mucosal abnormality that is associated with a statistical increased risk of developing oral cancer. Unfortunately, there are currently no tools available to accurately predict whether a patient in the early stages of oral carcinogenesis will develop oral cancer, being the presence and severity of epithelial dysplasia the histological marker universally applied for clinical practice. Nevertheless, this system presents relevant limitations related to imprecise and subjective assessments; therefore, emerging molecular biomarkers are under investigation. Among these biomarkers, retinoblastoma protein (pRb) is a well-recognized tumor suppressor in human oncogenesis, with roles linked to evading growth suppressors, a relevant hallmark of cancer. The loss of pRb expression regulates tumor initiation and early progression of neoplasms, and has been hypothesized to exert an oncogenic role during malignant transformation in early stages of oral carcinogenesis. Objective: The aim of this systematic review and meta-analysis was to qualitatively and quantitatively evaluate the current evidence on the significance of the loss of early stages of oral carcinogenesis in lesions diagnosed according to clinical and/or histopathological criteria and their evolution to oral cancer. Materials and Methods: We searched MEDLINE (through PubMed), Embase, Scopus and Web of Science for primary-level studies published before November 2024, designed as prospective or retrospective longitudinal cohorts, and not restricted by language or publication date. The risk of bias was critically assessed using the QUIPS tool. Meta-analyses, heterogeneity exploration, sensitivity and small-study effect analyses were conducted. Results: The inclusion criteria were met by six primary-level studies, which recruited 330 patients with OPMDs with follow-up data. The loss of pRb expression, assessed through immunohistochemistry, was significantly associated with a higher malignant transformation risk of OPMDs (RR = 1.92, 95%CI = 1.25–2.94, p = 0.003). The leukoplakia subgroup retained this significant association (p = 0.006), being the OPMD where the loss of pRb expression showed the best predictive value for malignant transformation (RR = 2.00, 95%CI = 1.22–3.29). Regarding the immunohistochemical technique and scoring methods, better performance and results were achieved by applying a cutoff point > 10% pRb-positive cells with nuclear staining (RR = 2.10, 95%CI = 1.30–3.38, 95%CI = 0.002). Conclussion: The present systematic review and meta-analysis supports that the loss of expression of the tumor suppressor pRb, assessed through immunohistochemistry, is a predictor of the malignant transformation risk of oral leukoplakias. Future studies are needed in other OPMDs following the recommendations provided based on current evidence gaps. [ABSTRACT FROM AUTHOR]

Simple Summary: Regucalcin plays a multifunctional role in cellular regulation in maintaining cell homeostasis and has been implicated in several metabolic disorders and diseases. In particular, regucalcin is a novel suppressor in several cancer types. Regucalcin plays a potential role in suppressing carcinogenesis. The survival time of cancer patients is prolonged with increased expression of regucalcin in the tumor tissues. The migration, invasion, and bone metastatic activity of cancer cells are blocked by the overexpression of regucalcin, thereby promoting dormancy in cancer patients. Notably, regucalcin is found in serum and extracellular fluids. Extracellular regucalcin has been shown to suppress the growth and bone metastatic activity of human cancer cells, suggesting that it plays an important role as a suppressor in the tumor microenvironment of cancer cells. Alteration of serum regucalcin levels under physiological and pathophysiological conditions may influence cancer activity in the microenvironment. This review discusses the potential role of extracellular regucalcin in cancer cell activity as a potential suppressor in the cancer microenvironment, proposing the role of exogenous regucalcin in cancer prevention and therapy. The regucalcin gene is located on the X chromosome, comprising seven exons and six introns. This gene and protein are expressed in various tissues and cells and is predominantly expressed in human liver, kidney, and adrenal tissues. Regucalcin gene expression is enhanced via a mechanism mediated by several signaling molecules and transcription factors. Regucalcin plays a multifunctional role in cellular regulation in maintaining cell homeostasis. In addition, regucalcin has been implicated in several metabolic disorders and diseases. In particular, regucalcin plays a role as a novel suppressor in several types of cancer patients. Increased expression of regucalcin suppresses the growth of human cancer cells, suggesting its pivotal role in suppressing tumor development. The survival time of cancer patients is prolonged with increased expression of regucalcin in the tumor tissues. The adhesion, migration, invasion, and bone metastatic activity of cancer cells are blocked by the overexpression of regucalcin, promoting dormancy in cancer patients. Interestingly, regucalcin is also found in human serum, suggesting its character as a novel biomarker in various diseases. This extracellular regucalcin has been shown to suppress human cancer cells' growth and bone metastatic activity. Thus, extracellular regucalcin may play a vital role as a suppressor of human cancer activity. Alteration of the serum regucalcin levels in physiological and pathophysiological conditions may influence the activity of cancer cells in the microenvironment. This review will discuss the potential role of extracellular regucalcin in cancer cell activity as a critical suppressor in the cancer microenvironment. [ABSTRACT FROM AUTHOR]

Mono-ubiquitination of lysine 18 on histone H3 (H3K18ub), catalyzed by UHRF1, is a DNMT1 docking site that facilitates replication-coupled DNA methylation maintenance. Its functions beyond this are unknown. Here, we genomically map simultaneous increases in UHRF1-dependent H3K18ub and SUV39H1/H2-dependent H3K9me3 following DNMT1 inhibition. Mechanistically, transient accumulation of hemi-methylated DNA at CpG islands facilitates UHRF1 recruitment and E3 ligase activity toward H3K18. Notably, H3K18ub enhances SUV39H1/H2 methyltransferase activity and, in colon cancer cells, nucleates new H3K9me3 domains at CpG island promoters of DNA methylation-silenced tumor suppressor genes (TSGs). Disrupting UHRF1 enzyme activity prevents H3K9me3 accumulation while promoting PRC2-dependent H3K27me3 as a tertiary layer of gene repression in these regions. By contrast, disrupting H3K18ub-dependent SUV39H1/H2 activity enhances the transcriptional activating and antiproliferative effects of DNMT1 inhibition. Collectively, these findings reveal roles for UHRF1 and H3K18ub in regulating a hierarchy of repressive histone methylation signaling and rationalize a combination strategy for epigenetic cancer therapy. [Display omitted] • DNA hypomethylation leads to UHRF1-dependent increases in H3K18ub and H3K9me3 • Hemi-methylated DNA accumulation promotes H3K18ub that enhances SUV39H1/H2 activity • Disrupting UHRF1 activity prevents H3K9me3 accumulation but promotes PRC2 activity • Targeting H3K18ub stimulation of SUV39H1/H2 enhances DNMT1 inhibitor efficacy Liu et al. report that DNMT1 inhibition causes transient accumulation of hemi-methylated DNA at CpG islands, which stimulates UHRF1-mediated H3K18ub. This enhances SUV39H1/H2 activity, nucleates new H3K9me3 domains, and impedes PRC2 activity at DNA-methylation-silenced TSG promoters. Targeting this previously unrecognized H3K18ub-H3K9me3 crosstalk offers new strategies to enhance DNMT1 inhibitor therapy. [ABSTRACT FROM AUTHOR]

The genesis of hepatocellular carcinoma (HCC) is closely related to male factors and hyper-activated Ras signals. A transcriptomic database was established via RNA-Seq of HCC (T) and the adjacent precancerous liver tissue (P) of Hras12V transgenic mice (Ras-Tg, HCC model) and the normal liver tissue of wild-type mice (W) of both sexes. Comparative analysis within W, P, and T and correlation expression pattern analysis revealed common/unique cluster-enriched items towards HCC between the sexes. Specifically, the numbers of differentially expressed genes (DEGs) were much higher in females than in males, and tumor suppressor genes, such as p21Waf1/Cip1 and C6, were significantly higher in the female P. This finding denotes the higher sensitivity of female hepatocytes to the Ras oncogene and, therefore, the difficulty in developing HCC. Moreover, convergence in HCC between the sexes suggests the underlying mechanisms for the ineffectiveness of sex hormone therapies. Additionally, expression pattern analysis revealed that the DEGs and their relevant pathways were either positively or negatively associated with the HCC/Ras oncogene. Among them, the vital role of glutathione metabolism in HCC was established. This work provides a basis for future research on elucidating the underlying mechanisms, selecting the diagnostic biomarker, and planning the clinical therapy in HCC. [ABSTRACT FROM AUTHOR]

The article in the Blood Cancer Journal explores the genetics of extramedullary disease (EMD) in multiple myeloma (MM) through whole genome sequencing. The study reveals that EMD is genetically complex, with no single unifying factor, and frequently involves oncogenes like BRAF, NRAS, KRAS, and MYC. Mutational signature analysis suggests two distinct mechanisms of mutagenesis in EMD, with MAPK-driven EMD patients showing better overall survival. The study highlights potential therapeutic vulnerabilities and the need for targeted therapies in EMD. [Extracted from the article]

Despite advances in various chemotherapy regimens, current therapeutic options are limited for ovarian cancer patients. Oxidative stress-induced growth inhibitor 1 (OSGIN1), which is a tumor suppressor gene known to regulate the cellular stress response and apoptosis, is associated with ovarian cancer development. However, the underlying mechanisms involved in ferroptosis regulation have not been elucidated. Thus, this study aimed to investigate the effect and underlying regulatory mechanism of the OSGIN1 gene on ovarian cancer cells. Our results demonstrated that loss of the OSGIN1 gene promoted ovarian cancer growth and conferred resistance to drug-induced ferroptosis. Mechanistically, the loss of OSGIN1 activates AMPK signaling through ATM, leading to the upregulation of SLC2A3, which protects cells from ferroptosis and renders them insensitive to ferroptosis inducers. Notably, an SLC2A3-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on ovarian cancer patient-derived xenograft tumors. Overall, anti-SLC2A3 therapy is a promising method to improve ovarian cancer treatment by targeting ferroptosis. [ABSTRACT FROM AUTHOR]

Background: PTEN hamartoma tumor syndrome (PHTS) has evolved into an umbrella term for a range of syndromes, characterized by loss-of-function variants in the phosphatase and tensin homolog (PTEN) tumor suppressor gene on chromosome 10q23.31. This can result in a lifelong tumor predisposition in patients. Often, the syndrome is diagnosed in early childhood because of macrocephaly, dermatological findings, or development delay. Since the correlation between phenotype and genotype is weak, and the penetrance is age-dependent, this poses the question of the appropriate timing of potentially invasive and burdensome examinations for early cancer detection. Case: The present report describes an infant with cleft palate associated with PHTS, a rare occurrence, though the initial report of Cowden syndrome already pointed to oromaxillofacial abnormalities. The recent pediatric literature is reviewed to assess which clinical symptoms should raise suspicion of PHTS and may then lead to early genetic counseling. Conclusion: Since the amount of prospective data remains limited, and the estimation of tumor risk during infancy and adulthood is very difficult, we advocate for early and broad genetic testing in suspected cases, to gain more insights into this rare disease and allow for better counseling for patients and their families. [ABSTRACT FROM AUTHOR]

Background: TSPX is an X-linked tumor suppressor that was initially identified in non-small cell lung cancer (NSCLC) cell lines. However, its expression patterns and downstream mechanisms in NSCLC remain unclear. This study aims to investigate the functions of TSPX in NSCLC by identifying its potential downstream targets and their correlation with clinical outcomes. Methods: RNA-seq transcriptome and pathway enrichment analyses were conducted on the TSPX-overexpressing NSCLC cell lines, A549 and SK-MES-1, originating from lung adenocarcinoma and squamous cell carcinoma subtypes, respectively. In addition, comparative analyses were performed using the data from clinical NSCLC specimens (515 lung adenocarcinomas and 502 lung squamous cell carcinomas) in the Cancer Genome Atlas (TCGA) database. Results: TCGA data analysis revealed significant downregulation of TSPX in NSCLC tumors compared to adjacent non-cancerous tissues (Wilcoxon matched pairs signed rank test p < 0.0001). Notably, the TSPX expression levels were inversely correlated with the cancer stage, and higher TSPX levels were associated with better clinical outcomes and improved survival in lung adenocarcinoma, a subtype of NSCLC (median survival extended by 510 days; log-rank test, p = 0.0025). RNA-seq analysis of the TSPX-overexpressing NSCLC cell lines revealed that TSPX regulates various genes involved in the cancer-related signaling pathways and cell viability, consistent with the suppression of cell proliferation in cell culture assays. Notably, various potential downstream targets of TSPX that correlated with patient survival (log-rank test, p = 0.016 to 4.3 × 10−10) were identified, including EGFR pathway-related genes AREG, EREG, FOSL1, and MYC, which were downregulated. Conclusions: Our results suggest that TSPX plays a critical role in suppressing NSCLC progression by downregulating pro-oncogenic genes, particularly those in the EGFR signaling pathway, and upregulating the tumor suppressors, especially in lung adenocarcinoma. These findings suggest that TSPX is a potential biomarker and therapeutic target for NSCLC management. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explores the structural and stability impacts of rare genetic and somatic mutations in two glutathione peroxidase proteins, GPx7 and GPx8, which play crucial roles in cellular stress responses. This study aims to identify how these mutations affect protein stability, as these changes are often associated with cancers and other complex diseases. Using advanced computational methods, this research analyzed thousands of potential mutations to predict their effects on protein function. The findings reveal that destabilizing mutations are more likely to be associated with diseases, providing insights into the molecular mechanisms of cancer development. By focusing on high-impact mutations, this study provides a foundation for developing targeted therapies and better understanding the molecular basis of diseases associated with these proteins. Background/Objectives: Somatic and genetic mutations in glutathione peroxidases (GPxs), including GPx7 and GPx8, have been linked to intellectual disability, microcephaly, and various tumors. GPx7 and GPx8 evolved the latest among the GPx enzymes and are present in the endoplasmic reticulum. Although lacking a glutathione binding domain, GPx7 and GPx8 possess peroxidase activity that helps the body respond to cellular stress. However, the protein mutations in these peroxidases remain relatively understudied. Methods: By elucidating the structural and stability consequences of missense mutations, this study aims to provide insights into the pathogenic mechanisms involved in different cancers, thereby aiding clinical diagnosis, treatment strategies, and the development of targeted therapies. We performed saturated computational mutagenesis to analyze 2926 and 3971 missense mutations of GPx7 and GPx8, respectively. Results: The results indicate that G153H and G153F in GPx7 are highly destabilizing, while E93M and W142F are stabilizing. In GPx8, N74W and G173W caused the most instability while S70I and S119P increased stability. Our analysis shows that highly destabilizing somatic and genetic mutations are more likely pathogenic compared to stabilizing mutations. Conclusions: This comprehensive analysis of missense mutations in GPx7 and GPx8 provides critical insights into their impact on protein structure and stability, contributing to a deeper understanding of the roles of somatic mutations in cancer development and progression. These findings can inform more precise clinical diagnostics and targeted treatment approaches for cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we sought to understand the role of NF2 gene mutation in the carcinogenesis of sporadic cancers. NF2 gene mutations are noted in several central nervous system tumors, solid-organ tumors, and skin cancers. We conducted a literature review on eleven different cancers with NF2 gene mutation involvement, summarizing the extent of association and specific biological pathways thought to be affected by NF2 mutations. We synthesized studies across several oncologic fields to consolidate what we know about NF2 gene mutations in cancer development. The Hippo signaling pathway is a biological pathway that is involved in eight of the eleven NF2-mutated cancers studied in this review. Although NF2 mutation has a known interaction with the Hippo signaling pathway, the specific details of this interface remain a topic for further studies. Background/Objectives: With the rise in prevalence of diagnostic genetic techniques like RNA sequencing and whole exome sequencing (WES), as well as biological treatment regiments for cancer therapy, several genes have been implicated in carcinogenesis. This review aims to update our understanding of the Neurofibromatosis 2 (NF2) gene and its role in the pathogenesis of various cancers. Methods: A comprehensive search of five online databases yielded 43 studies that highlighted the effect of sporadic NF2 mutations on several cancers, including sporadic meningioma, ependymoma, schwannoma, mesothelioma, breast cancer, hepatocellular carcinoma, prostate cancer, glioblastoma, thyroid cancer, and melanoma. Of note were key biological pathways implicated in cancer formation resulting from sporadic NF2 mutations. Results: NF2 gene mutations are implicated in over 11 different cancers, including several CNS tumors, soli-organ tumors, and skin cancer. NF2 acts as a driver mutation in some cancers, as a non-driver mutation in some cancers, and has simple associated mutations with other cancers. In terms of biological pathway involvement, 8 of the 11 cancers with NF2 mutations show evidence of Hippo signaling cascade involvement. Conclusions: Several cancers characterized by mutations in the NF2 gene have associations with the Hippo signaling pathway. However, future studies remain to be done to further elucidate the role of the Hippo signaling pathway in the carcinogenesis of human NF2-mutant tumors. The findings of this review provide insights into the role of NF2 mutations in cancers, Hippo signaling in NF2-mutant cancers, and current gaps in our knowledge regarding the two. [ABSTRACT FROM AUTHOR]

Cancer is a complex genetic disorder characterized by abnormalities in both coding and regulatory non-coding RNAs. microRNAs (miRNAs) are key regulatory non-coding RNAs that modulate cancer development, functioning as both tumor suppressors and oncogenes. miRNAs play critical roles in cancer progression, influencing key processes such as initiation, promotion, and metastasis. They exert their effects by targeting tumor suppressor genes, thereby facilitating cancer progression, while also inhibiting oncogenes to prevent further disease advancement. The miR-10 family, particularly miR-10a-5p and miR-10b-5p (miR-10a/b-5p), is notably involved in cancer progression. Intriguingly, their functions can differ across different cancers, sometimes promoting and at other times suppressing tumor growth depending on the cancer type and target genes. This review explores the dual roles of miR-10a/b-5p as tumor-suppressive miRNAs (TSmiRs) or oncogenic miRNAs (oncomiRs) in various cancers by examining their molecular and cellular mechanisms and their impact on the tumor microenvironment. Furthermore, we discuss the potential of miR-10a/b-5p as therapeutic targets, emphasizing miRNA-based strategies for cancer treatment. The insights discussed in this review aim to advance our understanding of miR-10a/b-5p's roles in tumor biology and their application in developing innovative cancer therapies. [ABSTRACT FROM AUTHOR]

The document discusses the advances in molecular mechanisms and therapeutic strategies in colorectal cancer, highlighting the complexity of the disease and the importance of precision medicine. It explores the molecular drivers, prognostic markers, and the role of the tumor microenvironment and microbiome in CRC progression. The text also delves into chemotherapy, targeted therapy, immunotherapy, liquid biopsy techniques, and nanoparticle-based therapies as promising avenues for personalized treatment. Overall, the document emphasizes the transformative shift towards precision medicine in CRC treatment, offering new hope for improved outcomes and survival rates. [Extracted from the article]

Aggressive variant prostate cancer (AVPC) is characterized by a molecular signature involving combined defects in TP53, RB1, and/or PTEN (AVPC-TSGs), identifiable through immunohistochemistry or genomic analysis. The reported prevalence of AVPC-TSG alterations varies widely, reflecting differences in assay sensitivity, treatment pressure, and disease stage evolution. Although robust clinical evidence is still emerging, the study of AVPC-TSG alterations in prostate cancer (PCa) is promising. Alterations in TP53, RB1, and PTEN, as well as the combined loss of AVPC-TSGs, may have significant implications for prognosis and treatment. These biomarkers might help predict responses to various therapies, including hormonal treatments, cytotoxic agents, radiotherapy, and targeted therapies. Understanding the impact of these molecular alterations in patients with PCa is crucial for personalized management. In this review, we provide a comprehensive overview of the emerging prognostic and predictive roles of AVPC-TSG alterations across PCa stages. Moreover, we discuss the implications of different methods used for detecting AVPC-TSG alterations and summarize factors influencing their prevalence. As our comprehension of the genomic landscape of PCa disease deepens, incorporating genomic profiling into clinical decision making will become increasingly important for improving patient outcomes. [ABSTRACT FROM AUTHOR]

Cancer cells undergo metabolic rewiring to support rapid proliferation and survival in challenging environments. Glutamine is a preferred resource for cancer metabolism, as it provides both carbon and nitrogen for cellular biogenesis. Recent studies suggest the potential anticancer activity of amino acid analogs. Some of these analogs disrupt cellular nucleotide synthesis, thereby inhibiting the formation of DNA and RNA in cancer cells. In the present study, we investigated the anticancer properties of Acivicin and Azaserine in the breast cancer MCF-7 cell line, comparing their effects to those on the non-tumorigenic MCF-10 epithelial cell line in vitro. Interestingly, at lower concentrations, both Acivicin and Azaserine showed potent inhibition of MCF-7 cell proliferation, as assessed by the MTT assay, without detectable toxicity to normal cells. In contrast, Sorafenib (Nexavar), a commonly used drug for solid tumors, showed harmful effects on normal cells, as indicated by increased lactate dehydrogenase (LDH) production in treated cells. Furthermore, unlike Sorafenib, treatment with Acivicin and Azaserine significantly affected apoptotic signaling in treated cells, indicating the role of both amino acid analogs in activating programmed cell death (PCD), as assessed by the Annexin-V assay, DAPI staining, and the relative expression of tumor suppressor genes PTEN and P53. ELISA analysis of MCF-7 cells revealed that both Acivicin and Azaserine treatments promoted the production of anti-inflammatory cytokines, including IL-4 and IL-10, while significantly reducing the production of tumor necrosis factor alpha (TNF-α). Mechanistically, both Acivicin and Azaserine treatment led to a significant reduction in the expression of glutamine synthetase (GS) at both the RNA and protein levels, resulting in a decrease in intracellular glutamine concentrations over time. Additionally, both treatments showed comparable effects on Raf-1 gene expression and protein phosphorylation when compared with Sorafenib, a Raf-1 inhibitor. Moreover, docking studies confirmed the strong binding affinity between Acivicin, Azaserine, and glutamine synthetase, as evidenced by their docking scores and binding interactions with the enzyme crystal. Collectively, these findings provide evidence for the anticancer activity of the two amino acid analogs Acivicin and Azaserine as antagonists of glutamine synthetase, offering novel insights into potential therapeutic strategies for breast cancer. [ABSTRACT FROM AUTHOR]

Tetraspanin 32 (TSPAN32), a member of the tetraspanin superfamily, is one of several tumor-suppressing subtransferable fragments located in the imprinted gene domain of chromosome 11p15.5, a critical tumor-suppressor gene region. Although the biology of TSPAN32 remains largely unexplored, accumulating evidence suggests its involvement in hematopoietic functions. In this study, we performed a comprehensive analysis of the expression patterns and regulatory roles of TSPAN32. Notably, TSPAN32 is highly expressed in immune cells, particularly in natural killer (NK) cells and CD8+ T cells. The observed downregulation of TSPAN32 during immune cell activation highlights its potential role as a regulator of immune cell activation and metabolic adaptations, which are crucial for effective immune responses against pathogens and tumors. Moreover, the modulation of biological processes following TSPAN32 knockout further supports its critical role in regulating immune cell physiology and responses. These findings not only shed light on the biology of TSPAN32 but also provide the basis for exploring its diagnostic, prognostic, and therapeutic potential in autoimmune and inflammatory disorders, as well as in hematopoietic cancers. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) plays a pivotal role in neoplastic initiation and progression. Epigenetic machinery, governing the expression of core oncogenes and tumor suppressor genes in transformed cells, significantly contributes to tumor development at both primary and distant sites. Recent studies have illuminated how epigenetic mechanisms integrate external cues and downstream signals, altering the phenotype of stromal cells and immune cells. This remolds the area surrounding tumor cells, ultimately fostering an immunosuppressive microenvironment. Therefore, correcting the TME by targeting the epigenetic modifications holds substantial promise for cancer treatment. This review synthesizes recent research that elucidates the impact of specific epigenetic regulations—ranging from DNA methylation to histone modifications and chromatin remodeling—on stromal and immune cells within the TME. Notably, we highlight their functional roles in either promoting or restricting tumor progression. We also discuss the potential applications of epigenetic agents for cancer treatment, envisaging their ability to normalize the ecosystem. This review aims to assist researchers in understanding the dynamic interplay between epigenetics and the TME, paving the way for better epigenetic therapy. [ABSTRACT FROM AUTHOR]

Aim: The role of the zinc fingers and homeoboxes family (ZHX1–3), transcriptional repressors, through their subcellular localization in hepatocellular carcinoma (HCC), is not fully understood. The present study aimed to examine the differential nuclear and cytoplasmic expression of ZHXs in HCC tissues. Methods: Immunohistochemistry was utilized to detect the expression of ZHXs in 54 liver tissues from HCC (n = 33), hepatitis C (n = 16), and the normal liver tissue surrounding hepatic metastasis of colorectal cancer (n = 5). Next‐generation sequencing and digital polymerase chain reaction identified gene mutations associated with HCC. Kaplan–Meier curves were constructed to evaluate the relationship between ZHX expression and survival. The results were validated using data from The Cancer Genome Atlas. Univariate and multivariate Cox regression analyses were undertaken to identify independent prognostic factors. Results: High nuclear expression of ZHX1 was associated with poor overall survival (OS), while high nuclear expression of ZHX2 correlated with higher recurrence. Conversely, patients with high cytoplasmic expression of ZHX3 had lower recurrence and better OS. Hepatitis B virus‐associated HCC was related to high cytoplasmic expression of ZHX1, which was marginally related to telomerase reverse transcriptase (TERT) promoter mutation‐negative HCC. In contrast, low nuclear expression of ZHX3 was associated with TERT promoter mutation‐positive HCC and HCC patients over 70 years old. Conclusions: These results suggest that the expression and localization of different ZHXs may be related to HCC progression, potentially inferring genetic backgrounds such as TERT promoter mutation. Further studies on the relationship between HCC and ZHXs will enhance our understanding and control of HCC. [ABSTRACT FROM AUTHOR]

The p53 gene is an important tumour suppressor gene, which has an important impact on the early diagnosis of cancer. Here, inspired by the fact that single-stranded DNA (ss-DNA) can be nonspecifically adsorbed on the surface of nanogold, we report on a sensitive and cost-effective new method to detect the p53 gene by combining hybridization chain reaction (HCR) with gold nanoparticles. The long double helix structure generated by HCR could not be adsorbed on the nanogold surface after the addition of the p53 gene. When an appropriate amount of Na+ is introduced into the solution, the nanogold aggregates and the color of the solution changes from red to blueviolet. The sensor has a high sensitivity with a detection limit of 2 nM visible to the naked eye and a quantitative detection limit of 0.2 nM using a UV-visible spectrophotometer. Notably, by combining fluorescence spectroscopy and gel electrophoresis, the science and specificity of p53 gene-induced HCR is systematically validated. The use of an enzyme-free, label-free colorimetric method to detect the p53 gene greatly reduces the complexity and cost of the experiment. This study has a broad market application prospect and provides a new method for early mass screening of cancer genes. [ABSTRACT FROM AUTHOR]

Objective: Colorectal cancer (CRC) is a type of digestive system cancer. At the molecular level, some factors, including genetic and epigenetic factors, as well as various signaling pathways such as oxidative stress and inflammation, play an active role in the onset of CRC. Genetic and epigenetic mutations, particularly in oncogenes and tumor suppressor genes, occur during colorectal adenocarcinoma development as a result of a change in gastrointestinal epithelial cell proliferation and self-renewal rates. This study aimed to determine the genes and molecular mechanisms that play a role in the emergence of this disease by analyzing the CRC data. Material and methods: Microarray data selected for bioinformatics analysis is Gene Expression data stored with the code GSE110224 in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Gene expression analysis, functional clustering analysis, enrichment analysis, and pathway analysis were performed using this data set. Results: Analysis of raw transcriptomic data revealed 1770 common DEGs in CRC. While the expression level of 769 of these genes increased, the expression level of 1001 genes decreased. A Protein–protein interaction (PPI) network was created from the first 25 genes with increased expression levels and 11 signature genes were identified. Increased expression of REG1A, MMP3, FOXQ1 and CEMIP genes and decreased expression of AQP8, CA1, CLDN8, PYY, CA4, CEACAM7 and SLC30A10 genes were observed. Conclusions: This approach revealed a CRC-specific molecular profile and may provide some guidance for further investigation of potential biomarkers for diagnosis and prognosis prediction of CRC patients. [ABSTRACT FROM AUTHOR]

Cigarette smoking is a well-known risk factor inducing the development and progression of various diseases. Nicotine (NIC) is the major constituent of cigarette smoke. However, knowledge of the mechanism underlying the NIC-regulated stem cell functions is limited. In this study, we demonstrate that NIC increases the abundance and proliferative activity of murine intestinal stem cells (ISCs) in vivo and ex vivo. Moreover, NIC induces Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) and Notch signaling in ISCs via a7-nicotinic acetylcholine receptor (nAchR) and protein kinase C (PKC) activation; this effect was not detected in Paneth cells. The inhibition of Notch signaling by dibenzazepine (DBZ) nullified the effects of NIC on ISCs. NIC enhances in vivo tumor formation from ISCs after loss of the tumor suppressor gene Apc, DBZ inhibited NIC-induced tumor growth. Hence, this study identifies a NIC-triggered pathway regulating the stemness and tumorigenicity of ISCs and suggests the use of DBZ as a potential therapeutic strategy for treating intestinal tumors. [ABSTRACT FROM AUTHOR]

Cachexia and systemic organ wasting are metabolic syndrome often associated with cancer. However, the exact mechanism of cancer associated cachexia like syndrome still remain elusive. In this study, we utilized a scribble (scrib) knockdown induced hindgut tumor to investigate the role of JNK kinase in cachexia like syndrome. Scrib , a cell polarity regulator, also acts as a tumor suppressor gene. Its loss and mis-localization are reported in various type of malignant cancer-like breast, colon and prostate cancer. The scrib knockdown flies exhibited male lethality, reduced life span, systemic organ wasting and increased pJNK level in hindgut of female flies. Interestingly, knocking down of human JNK Kinase analogue, hep , in scrib knockdown background in hindgut leads to restoration of loss of scrib mediated lethality and systemic organ wasting. Our data showed that scrib loss in hindgut is capable of inducing cancer associated cachexia like syndrome. Here, we firstly report that blocking the JNK signaling pathway effectively rescued the cancer cachexia induced by scrib knockdown, along with its associated gut barrier disruption. These findings have significantly advanced our understanding of cancer cachexia and have potential implications for the development of therapeutic strategies. However, more research is needed to fully understand the complex mechanisms underlying this condition. [Display omitted] • Scrib knockdown (KD) in hindgut leads to systemic organ wasting and increased pJNK levels. • Study first time uncovers a significant link between Scrib cancer-associated cachexia and JNK pathway. • JNK knockdown in loss of scribble background restores normal physiology and alleviates cancer-associated cachexia. • Role of JNK signaling in cachexia opens up potential new avenues for therapeutic interventions in cancer treatment. [ABSTRACT FROM AUTHOR]

Background: The treatment of gastric cancer (GC) is still quite challenging. Yet, marine invertebrates have been found to produce a wide range of anticancer bioactive compounds that show promise in fighting cancer. The present study aimed to evaluate whether saponin derived from Holothuria leucospilata (H. Leucospilota), a species of sea cucumber, possesses anticancer activity against GC cells. Method: In this experimental study, the cytotoxic effect of H. Leucospilota-derived n-butanol fraction saponins (HLBS) sourced from the Persian Gulf on MKN45 GC cells was evaluated through tetrazolium salt and colony formation assays. The effect of HLBS on MKN45 cell migration, cell cycle, and apoptosis was assessed using a scratch assay, and flow cytometry, respectively. Hub genes of GC were identified through bioinformatics analysis. The effects of HLBS on the expression of the two top-ranked GC hub genes were measured using real-time polymerase chain reaction. Comparisons between groups were performed using the ANOVA test by GraphPad Prism software at the statistically significant P-value <0.05. Results: HLBS with an IC50 concentration of 75 µg/ml at 48 hours resulted in a significant decrease in cell viability, clonogenic ability (46.63% reduction, P < 0.01), and migration of MKN45 cells (74.5% reduction, P < 0.01). Moreover, HLBS led to an increase of approximately 21 and 13% in the S-phase and apoptotic cell populations, respectively. HLBS also upregulated the expression of CDH1, as a highly ranked hub gene associated with GC (P < 0.05). Conclusion: The inhibitory effect of HLBS on MKN45 cells suggests HLBS as a candidate for further drug discovery programs in GC research, and paves the way to introduce new anticancer HLBS synthetic derivatives. [ABSTRACT FROM AUTHOR]

Background: It is believed that anthracosis is one of the most important occupational diseases, mainly seen in the residents of industrial areas and coal mine workers. This bronchial disease is more common in Asia's rural areas, particularly in the Middle East. In this study, we examined the epidemiology and genetic factors affecting this disease and its relationship with different types of cancer. Methods: In this review article, we searched four databases (Pubmed, the Cochrane Database of Systematic Reviews, Embase and Scopus) up to June 3, 2022, for published articles on anthracosis, epidemiology, gene, and cancer. Non-published studies, studies not published in indexed journals or without peer review, and studies not available in English were all excluded. Results: The relationship between this disease and tobacco, smoking, air pollution, mycobacterium tuberculosis, gender, and indoor smoke was researched, and its prevalence was cited. Mutations in tumour suppressor genes such as P16 and P53 and expression levels of P16, CDH1, LUNX and RASSF1A genes were researched. Finally, this article discussed the relationship between anthracosis and cancers. Conclusions: According to the studied literature, antracotic people are more susceptible to pulmonary adenocarcinoma, hepatic nodules, renal cell carcinoma, and esophageal cancer. [ABSTRACT FROM AUTHOR]

F-box and WD repeat domain-containing 7 (FBXW7), formerly known as hCdc4, hAGO Fbw7, or SEL10, plays a specific recognition function in SCF-type E3 ubiquitin ligases. FBXW7 is a well-established cancer suppressor gene that specifically controls proteasomal degradation and destruction of many key oncogenic substrates. The FBXW7 gene is frequently abnormal in human malignancies especially in gastrointestinal cancers. Accumulating evidence reveals that mutations and deletions of FBXW7 are participating in the occurrence, progression and treatment resistance of human gastrointestinal cancers. Considering the current therapeutic challenges faced by gastrointestinal cancers, elucidating the biological function and molecular mechanism of FBXW7 can provide new perspectives and references for future personalized treatment strategies. In this review, we elucidate the key molecular mechanisms by which FBXW7 and its substrates are involved in gastrointestinal cancers. Furthermore, we discuss the consequences of FBXW7 loss or dysfunction in tumor progression and underscore its potential as a prognostic and therapeutic biomarker. Lastly, we propose potential therapeutic strategies targeting FBXW7 to guide the precision treatment of gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a highly aggressive and clinically challenging subtype of breast cancer, lacking the expression of estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. The absence of these receptors limits therapeutic options necessitating the exploration of novel treatment strategies. Epigenetic modifications, which include DNA methylation, histone modifications, and microRNA (miRNA) regulation, play a pivotal role in TNBC pathogenesis and represent promising therapeutic targets. This review delves into the therapeutic potential of epigenetic interventions in TNBC, with a focus on DNA methylation, histone modifications, and miRNA therapeutics. We examine the role of DNA methylation in gene silencing within TNBC and the development of DNA methylation inhibitors designed to reactivate silenced tumor suppressor genes. Histone modifications, through histone deacetylation and acetylation in particular, are critical in regulating gene expression. We explore the efficacy of histone deacetylase inhibitors (HDACi), which have shown promise in reversing aberrant histone deacetylation patterns, thereby restoring normal gene function, and suppressing tumor growth. Furthermore, the review highlights the dual role of miRNAs in TNBC as both oncogenes and tumor suppressors and discusses the therapeutic potential of miRNA mimics and inhibitors in modulating these regulatory molecules to inhibit cancer progression. By integrating these epigenetic therapies, we propose a multifaceted approach to target the underlying epigenetic mechanisms that drive TNBC progression. The synergistic use of DNA methylation inhibitors, HDACi, and the miRNA-based therapies offers a promising avenue for personalized treatment strategies, aiming to enhance the clinical outcome for patients with TNBC. [ABSTRACT FROM AUTHOR]

This study investigates the potential treatment of breast cancer utilizing Gentiana robusta King ex Hook. f. (QJ) through an integrated approach involving network pharmacology, molecular docking, and molecular dynamics simulation. Building upon prior research on QJ's chemical constituents, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the DAVID database. Network interactions and core genes were identified using Cytoscape 3.9.1. Key target genes, including Interleukin-6 (IL-6), tumour suppressor gene P53 (TP53), and epidermal growth factor receptor (EGFR), were selected for molecular docking with QJ's active components, 2′-O-β-D-glucopyranosyl-gentiopicroside and macrophylloside D, employing Schrodinger Maestro 13.5. Molecular dynamics (MD) simulations were performed using the Desmond program. A total of 270 intersection targets of active ingredients and diseases were identified, with three core targets determined through network topology screening. Enrichment analysis highlighted the involvement of QJ in breast cancer treatment, primarily through the hsa05200 cancer signaling pathway and the hsa04066 HIF-1 signaling pathway. Molecular docking and dynamics simulations demonstrated the close interaction of 2′-O-β-D-glucopyranosyl-gentiopicroside (QJ17) and macrophylloside D (QJ25) with IL6, TP53, and EGFR, and other target genes, showcasing a stabilizing effect. In conclusion, this study unveils the effective components and potential mechanisms of 2′-O-β-D-glucopyranosyl-gentiopicroside and macrophylloside D in breast cancer prevention and treatment. The identified components act on target genes such as IL6, TP53, and EGFR, regulating crucial pathways including the cancer signaling and Hypoxia-inducible factor 1 (HIF-1) signaling pathways. These findings provide valuable insights into the therapeutic potential of QJ in breast cancer management. However, further experimental research are needed to validate the computational findings of QJ. [ABSTRACT FROM AUTHOR]

Breast cancer (BRCA) is one of the pivotal causes of female death worldwide. And the morbidity and mortality of breast cancer have increased rapidly. Immune checkpoints are important to maintain immune tolerance and are regarded as important therapeutic targets. However, research for BRCA were limited to single immune checkpoint-related gene (ICG) and few studies have systematically explored expression profile of Immune checkpoint-related genes or attempted to construct a prognostic gene risk model based on immune checkpoint-related genes. We identified immune checkpoint-related differentially expressed genes (DEGs) in BRCA and normal breast tissues from TCGA database. A 7-gene signature was created by utilizing the univariate Cox regression model with least absolute shrinkage and selection operator (LASSO) Cox regression method. In addition, we conducted a nomogram to predict the prognostic significance. This tool enables quantitative prediction of patient prognosis, serving as a valuable reference for clinical decision-making, thereby improving patient outcomes. Relationships between our risk model and clinical indicators, TME (Tumor Microenvironment), immune cell infiltration, immune response and drug susceptibility were investigated. A set of in vitro cell assays was conducted to decipher the relationship between MAP2K6 and proliferation, invasion, migration, colony formation and apoptosis rate of breast cancer cells. As a result, we established a prognostic model composed of seven ICGs in BRCA. Based on the median risk score, BRCA patients were equally assigned into two groups of high- and low-risk. High-risk BRCA patients have poorer OS (overall survival) than low-risk patients. In addition, there were remarkable differences between these two groups in clinicopathological features, TME, immune cell infiltration, immune response and drug susceptibility. The results of GO and KEGG analyses indicated that DEGs between the high- and low-risk groups were involved in immune-related biological processes and pathways. GSEA analysis also showed that a number of immune-related pathways were notably enriched in the low-risk group. Finally, results of cell-based assays indicated that MAP2K6 may play a pivotal role in the initiation and progression of breast cancer as a tumor suppressor gene. In conclusion, we created a novel ICG signature that has the potential to predict the survival and drug sensitivity of BRCA patients. Furthermore, this study indicated that MAP2K6 may serve as a novel target for BRCA therapy. [ABSTRACT FROM AUTHOR]

Hypomethylating agents (HMAs) such as azacytidine and decitabine are FDA-approved chemotherapy drugs for hematologic malignancy. By inhibiting DNA methyltransferases, HMAs reactivate tumor suppressor genes (TSGs) and endogenous double-stranded RNAs (dsRNAs) that limit tumor growth and trigger apoptosis via viral mimicry. Yet, HMAs show limited effects in many solid tumors despite the strong induction of TSGs and dsRNAs. Here we show that targeting mitochondrial RNAs (mtRNAs) can enhance the HMA-mediated cell death in lung adenocarcinoma cells. We find that HMA treatment accompanies increased mtRNA levels and subsequent enhancement of metabolic activity, resulting in higher ATP production. Compromising the mitochondrial function by downregulating mature mtRNA expression increased cell death by HMAs. We further perform a CRISPR screening on mtRNA processing factors and find that mtRNA polymerase (POLRMT) and ElaC Ribonuclease Z 2 (ELAC2) depleted cells show increased sensitivity to HMAs by suppressing decitabine-triggered enhancement of ATP production. Moreover, we show that a small molecular inhibitor of POLRMT compromises the metabolic activity and synergistically enhances the cytotoxicity of HMAs. Our study unveils the insensitivity to HMAs through the elevation of mtRNAs and suggests mtRNA regulatory factors as potential synergistic targets to improve the therapeutic benefit of HMAs. [ABSTRACT FROM AUTHOR]

Standard first-line therapy for patients with metastatic non-small cell lung cancer (mNSCLC) without identified actionable mutations consists of regimens comprising immune checkpoint inhibitors (ICIs), alone or in combination with platinum-based chemotherapy (CTx). However, approximately 20–30% of patients with mNSCLC (including some patients with high tumor programmed cell death ligand-1 expression) display primary resistance to ICIs, either alone or in combination with CTx. Mutations in tumor suppressor genes serine/threonine kinase 11 (STK11), and Kelch-like ECH-associated protein 1 (KEAP1) often detected in patients with Kirsten rat sarcoma virus mutations, are associated with an aggressive disease phenotype and resistance to standard ICI regimens. Consequently, there is an important need for effective treatments for patients with NSCLC with STK11 or KEAP1 mutations. In this article, we describe new data on the prevalence of STK11 and KEAP1 mutations in a large clinical population, consider practicalities around the detection of these mutations using available biomarker testing methodologies, and describe experiences of managing some of these difficult-to-treat patients in our clinical practice. [ABSTRACT FROM AUTHOR]

Background: miRNAs play a critical role in the progression of various diseases, including oral squamous cell carcinoma (OSCC), which represents a major health concern and is one of the leading causes for new cancer cases worldwide. The miRNA dysregulation causes havoc and could be attributed to various factors, with epigenetic silencing of tumor suppressor genes being a major contributor to tumorigenesis. In this study, we have explored the tumor suppressive role of miR-198 in OSCC. Methods: The tumor suppressive effect of miR-198 is established using miRNA analysis in OSCC cell lines, patient samples and xenograft nude mice model. The relationship between the miR-198 and TOPORS is explored using bioinformatics analyses, qRT-PCR, dual-luciferase reporter assay, Western blotting and cancer hall marks assays. The hypermethylation of the MIR198 promoter is confirmed using bisulfite sequencing PCR. Results: We have found miR-198 to be upregulated in OSCC cells treated with 5-Azacytidine, a known DNA methyltransferase inhibitor. Upregulation of miR-198 in 5-Azacytidine treated OSCC cells appears to be due to methylation of the MIR198 promoter. Using bioinformatics analysis and dual-luciferase reporter assay, we have identified TOPORS (TOP1 binding arginine/serine rich protein, E3 ubiquitin ligase) as a novel gene target for miR-198. miR-198-mediated repression of TOPORS decreases cell proliferation and anchorage-independent growth and enhances apoptosis of OSCC cells, which is dependent on the presence of the 3′UTR in TOPORS. An inverse correlation between the expression levels of miR-198 and TOPORS is observed in OSCC patient samples, highlighting the biological relevance of their interaction. Delivery of a synthetic miR-198 mimic to OSCC cells results in a significant decrease in xenograft size in nude mice, potentiating its use in therapeutics. Conclusions: These results suggest that miR-198 is epigenetically silenced in OSCC, which promotes tumor growth, in part, by upregulating the levels of TOPORS. [ABSTRACT FROM AUTHOR]

Simple Summary: Connexin-43 (Cx43) is known to be involved in Gap Junctional Intercellular Communication (GJIC). However, Cx43's non-canonical functions, encompassing signaling pathways elicited by its C-terminal tail and hemichannel activity, have gained traction in cancer biology. This review article focuses on the pro-tumorigenic implications of Cx43's non-GJIC functions and explores Cx43-dependent mechanisms contributing to cancer progression. Connexin-43 (Cx43) is the most characterized gap junction protein, primarily involved in the Gap Junctional Intercellular Communication (GJIC) between adjacent cells to facilitate molecule exchange and the formation of a signaling network. It is increasingly evident that the importance of Cx43 is not only limited to its GJIC function, but rather includes its role in connecting the intracellular and extracellular environment by forming membrane hemichannels, as well as its intracellular signaling function mediated by its C-terminal tail (Cx43-CT). Notably, Cx43 has been implicated in a variety of cancers, with earlier notions suggesting a tumor-suppressor function, whereas new studies shed light on its pro-tumorigenic role. Moreover, apart from GJIC-based activities, the relevance of the non-canonical functions of Cx43 in tumor progression is being actively studied. This review provides an analysis of the current research on the pro-tumorigenic roles of Cx43, with a focus on Cx43-CT interactions and the function of hemichannels in cancer progression. A better understanding of the multifaceted functions of Cx43 in cancer biology could foster its recognition as a pivotal target for the development of innovative therapeutic strategies. [ABSTRACT FROM AUTHOR]

To explore an alternative strategy to chemotherapy to combat oral cancer, natural products and their derivates constitute one promising approach. In the last previous study, we have demonstrated the potential anti-tumor properties of anethole; an aromatic compound abundantly present in nature that serves as a major active ingredient found in plants like anise and fennel. In the current study, we aimed to investigate how this molecule inhibits oral cancer cell proliferation and induces apoptosis. This will be carried out by a transcriptomic study of its effects on the expression profile of cell cycle and apoptosis regulation genes in gingival cancer cells. cell cycle. Ca9-22 cells were treated with 10 μM of anethole (IC50) and cell proliferation was evaluated by MTT assay. The percentage of cells in different stages of the cell cycle was measured by flow cytometry. Cytotoxicity was evaluated by LDH assay and apoptosis was investigated by Pi/Annexin V assay following 24-hour treatment. Furthermore, we employed PCR array analysis to investigate alterations in the expression levels of oncogenes and tumor suppressor genes associated with cell cycle regulation and apoptosis. Finally, Gene-gene interactions were examined using the Gene MANIA database. Our findings demonstrate that anethole significantly attenuated the proliferation of Ca9-22 cells, leading to disturbances in cell cycle progression and eliciting cellular toxicity and apoptosis. By a double normalizing with two housekeeping genes (Actin and GAPDH), we show that, treatment with 10 μM of anethole alters (more than two-fold) the expression of 13 genes involved in the control of the cell cycle (8 were up regulated and 5 were down regulated) and 7 genes involved in the regulation of apoptosis (4 were up regulated and 3 downregulated by anethole). Finally, each group of genes modulated by anethole forms a network of connections between them or with other genes. Our study suggests that anethole holds promise as a potential alternative treatment for oral cancer by its ability to modify numerous oncogenes and tumor suppressor genes implicated in the cell cycle regulation and induction of apoptosis in oral cancer cells. These findings underscore the significance of further research into the potential therapeutic application of anethole as an alternative drug for managing oral cancer. [ABSTRACT FROM AUTHOR]

Enhancer of zeste homolog 2 (EZH2) is a methyltransferase involved in cell cycle regulation, cell differentiation, and cell death and plays a role in modulating the immune response. Although it mainly functions by catalyzing the tri-methylation of H3 histone on K27 (H3K27), to inhibit the transcription of target genes, EZH2 can directly methylate several transcription factors or form complexes with them, regulating their functions. EZH2 expression/activity is often dysregulated in cancer, contributing to carcinogenesis and immune escape, thereby representing an important target in anti-cancer therapy. This review summarizes some of the mechanisms through which EZH2 regulates the expression and function of tumor suppressor genes and oncogenic molecules such as STAT3, mutant p53, and c-Myc and how it modulates the anti-cancer immune response. The influence of posttranslational modifications on EZH2 activity and stability and the possible strategies leading to its inhibition are also reviewed. [ABSTRACT FROM AUTHOR]

In almost all cancers, the p53 pathway is disabled and cancer cells survive. Hence, it is crucially important to induce cell death independent of p53 in the treatment of cancers. The transcription factor E2F1 is controlled by binding of the tumor suppressor pRB, and induces apoptosis by activating the ARF gene, an upstream activator of p53, when deregulated from pRB by loss of pRB function. Deregulated E2F1 can also induce apoptosis, independent of p53, via other targets such as TAp73 and BIM. We searched for novel E2F1-interacting proteins and identified the RNA helicase DEAD/H box 5 (DDX5), which also functions as a transcriptional coactivator. In contrast to the reported growth-promoting roles of DDX5, we show that DDX5 suppresses cell growth and survival by augmentation of deregulated E2F1 activity. Over-expression of DDX5 enhanced E2F1 induction of tumor suppressor gene expression and cell death. Conversely, shRNA-mediated knockdown of DDX5 compromised both. Moreover, DDX5 modulated E2F1-mediated cell death independent of p53, for which DDX5 also functions as a coactivator. Since p53 function is disabled in almost all cancers, these results underscore the roles of DDX5 in E2F1-mediated induction of cell death, independent of p53, and represent novel aspects for the treatment of p53-disabled cancer cells. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions The inactivation of tumor suppressor genes (TSGs) caused by abnormal DNA methylation is confirmed to be widely present in oral potential malignant diseases (OPMDs). Carotenoids like lycopene and astaxanthin can regulate DNA methylation and exert anticancer effects. Therapeutic effect of astaxanthin in OPMDs and oral squamous cell carcinoma (OSCC) models is confirmed, but the relationship between the anti‐cancer ability of astaxanthin and its DNA methylation regulation ability remains unclear.Whole‐genome bisulfite sequencing (WGBS) were used to provide biological information associated with DNA methylation. Methylation specific PCR was used to detect the methylation level of specific sites. Related markers were evaluated by qRT‐PCR and western blot. CCK8 assay, cell scratch assay, flow cytometric analysis were performed to investigate the cell viability, migration, cell cycle, and apoptosis after treated with concentrations of astaxanthin.WGBS revealed that HOXA3 and SOX1 were the TSGs with significant differences in promoter CpG methylation of oral dysplastic keratinocytes (DOK) cells. After treatment with 8 μM astaxanthin, the promoter CpG methylation levels of the TSGs were significantly reduced, resulting in the increase in gene expression. The overall effect of astaxanthin on DOK cells is inhibiting cell viability, reducing cell migration, leading to cell cycle G0/G1 arrest, and promoting apoptosis.This study confirmed significant differences in DNA methylation patterns among oral normal, dysplastic, and cancerous cells. Astaxanthin can reduce the promoter CpG methylation level of TSGs by reducing DNA methyltransferase 1 protein expression level, upregulating mRNA and protein expression, and subsequently modulating the biological behavior of DOK. [ABSTRACT FROM AUTHOR]