Cancer-related Signaling Pathways Research Articles

The X-Linked Tumor Suppressor TSPX Regulates Genes Involved in the EGFR Signaling Pathway and Cell Viability to Suppress Lung Adenocarcinoma

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.

Glucosinolates and Their Hydrolytic Derivatives: Promising Phytochemicals With Anticancer Potential.

Recent research has increasingly focused on phytochemicals as promising anticancer agents, with glucosinolates (GSLs) and their hydrolytic derivatives playing a central role. These sulfur-containing compounds, found in plants of the Brassicales order, are converted by myrosinase enzymes into biologically active products, primarily isothiocyanates (ITCs) and indoles, which exhibit significant anticancer properties. Indole-3-carbinol, diindolylmethane, sulforaphane (SFN), phenethyl isothiocyanate (PEITC), benzyl isothiocyanate, and allyl isothiocyanate have shown potent anticancer effects in animal models, particularly in breast, prostate, lung, melanoma, bladder, hepatoma, and gastrointestinal cancers. Clinical studies further support the chemopreventive effects of SFN and PEITC, particularly in detoxifying carcinogens and altering biochemical markers in cancer patients. These compounds have demonstrated good bioavailability, low toxicity, and minimal adverse effects, supporting their potential therapeutic application. Their anticancer mechanisms include the modulation of reactive oxygen species, suppression of cancer-related signaling pathways, and direct interaction with tumor cell proteins. Additionally, semi-synthetic derivatives of GSLs have been developed to enhance anticancer efficacy. In conclusion, GSLs and their derivatives offer significant potential as both chemopreventive and therapeutic agents, warranting further clinical investigation to optimize their application in cancer treatment.

Pathological roles of lncRNA HOTAIR in liver cancer: An updated review.

Liver cancer ranks as the sixth most prevalent form of cancer and stands as the fourth leading cause of cancer-related fatalities on a global scale. The two primary types of liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). While ICC originates from the bile ducts, HCC develops from hepatocytes, which are the primary functional cells of the liver. In cases where liver cancer is detected in its early stages, it can be effectively treated through locoregional interventions such as surgical resection, Radiofrequency Ablation, Transarterial chemoembolization, or liver transplantation. However, HCC is typically diagnosed at advanced stages, rendering these treatment options ineffective due to the unresectable nature of the tumor. LncRNAs, a novel class of RNA molecules and epigenetic regulators, have emerged as key players in the development and advancement of different types of tumors. They exert their influence by regulating the expression of downstream genes in cancer-related signaling pathways, thereby promoting the proliferation, migration, and invasion of tumor cells. Additionally, these transcripts have the ability to modify the activity and expression of tumor suppressors and oncogenes, further contributing to tumorigenesis. Recently, growing numbers of experiments have demonstrated the elevated expression of HOX antisense intergenic RNA (HOTAIR), a spliced and poly-adenylated lncRNA, in liver cancers and its association with cancer patient's prognosis and overall survival, as well as tumor cells' growth, metastasis, and resistance to therapies. This updated review will summarize molecular pathways by which lncRNA HOTAIR promotes liver cancer development, and highlight its diagnostic and therapeutic potential, though.

Integrated Transcriptomic and Proteomic Analyses of Antler Growth and Ossification Mechanisms.

Antlers are the sole mammalian organs capable of continuous regeneration. This distinctive feature has evolved into various biomedical models. Research on mechanisms of antler growth, development, and ossification provides valuable insights for limb regeneration, cartilage-related diseases, and cancer mechanisms. Here, ribonucleic acid sequencing (RNA-seq) and four-dimensional data-independent acquisition (4D DIA) technologies were employed to examine gene and protein expression differences among four tissue layers of the Chinese milu deer antler: reserve mesenchyme (RM), precartilage (PC), transition zone (TZ), cartilage (CA). Overall, 4611 differentially expressed genes (DEGs) and 2388 differentially expressed proteins (DEPs) were identified in the transcriptome and proteome, respectively. Among the 828 DEGs common to both omics approaches, genes from the collagen, integrin, and solute carrier families, and signaling molecules were emphasized for their roles in the regulation of antler growth, development, and ossification. Bioinformatics analysis revealed that in addition to being regulated by vascular and nerve regeneration pathways, antler growth and development are significantly influenced by numerous cancer-related signaling pathways. This indicates that antler growth mechanisms may be similar to those of cancer cell proliferation and development. This study lays a foundation for future research on the mechanisms underlying the rapid growth and ossification of antlers.

Target-based drug repositioning in papillary renal cell carcinoma with TFE3 fusion

Papillary renal cell carcinoma (PRCC) is the second most common subtype of renal cell carcinoma. Recurrent transcription factor E3 (TFE3) fusions have been identified in PRCC. Although patients with TFE3 fusions show relatively aggressive phenotypes, no effective targeted therapies have been developed. In this study, we aimed to identify putative therapeutic targets through systematic bioinformatic analysis of PRCC with TFE3 fusion. We identified TFE3 fusion cases (n = 6) and controls (n = 282) in The Cancer Genome Atlas database. A total of 1,314 differentially expressed genes were extracted. An overrepresentation analysis revealed cancer-related signaling pathways, which were categorized to 13 cancer-related pathways, including nuclear factor-erythroid factor 2-related factor 2 (NRF2)-, G protein-coupled receptor (GPCR) signaling-, inflammatory response-, development-, and insulin-like growth factor-related pathways. A network analysis and literature review were performed using drug-target databases to identify putative applicable drugs. We identified several promising drug candidates for PRCC with TFE3 fusion, including amrubicin, BCL6 inhibitors (79-6, BI-3812), cetuximab, epirubicin, gemcitabine, ipilimumab, linsitinib, olaparib, Orencia, paclitaxel, panitumumab, sorafenib, and tamoxifen. Our suggested strategy can help bridge the gap between transcriptome studies and the choice of therapeutic agents. Further experimental validation is needed to improve the efficacy of precision medicine for PRCC.

Integrated analysis of disulfidptosis-related genes SLC7A11, SLC3A2, RPN1 and NCKAP1 across cancers

Disulfidptosis, a newly identified form of regulated cell death associated with disruption of disulfide bond formation in the endoplasmic reticulum, involves the dysregulation of disulfidptosis-related genes (DRGs) that may contribute to cancer development and progression. However, the molecular mechanisms and clinical implications of DRGs in different cancer types remain poorly characterized. Therefore, in this comprehensive study, we investigated the expression, prognostic value, and functional roles of four recently identified DRGs (SLC7A11, SLC3A2, RPN1, and NCKAP1) across various cancers. Especially, in clinical samples of glioblastoma, we found that RPN1 was significantly correlated with patient survival. Through mutation landscape analysis, we identified diverse missense mutations in these DRGs, with NCKAP1 exhibiting the highest mutation frequency (5.9% in skin cutaneous melanoma). Additionally, we observed positive correlations between these DRGs and tumor stemness (DNAss DNA stemness score and RNAss RNA stemness score) as well as RNA modifications, particularly m6A modification, in several cancer types. Furthermore, high expression of SLC7A11, RPN1, and NCKAP1 was positively associated with infiltration of T-helper type 2 (Th2) cells in various cancers, while high expression of SLC7A11, SLC3A2, and RPN1 correlated with tumor mutational burden (TMB) in 10, 4, and 8 tumor types, respectively. Utilizing a protein–protein interaction network, we identified the RHO GTPases Activate WASPs and WAVEs pathway as significantly enriched, suggesting the involvement of these DRGs in cancer-related signaling pathways. Collectively, our findings provide novel insights into the molecular mechanisms and clinical implications of DRGs in pan-cancer, highlighting their potential as biomarkers and therapeutic targets for cancer treatment.

<b>Computational Analysis to Identify Novel Drug Targets for Esophageal Cancer</b>

Cancer is a multigene and widespread disease. Increasing drug resistance leads to the development of new therapeutic targets. Recent research indicates that various cellular components called Stress Granules (SGs) are engaged in the cancer-related signaling pathway. The phosphoinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, considered a master regulator in cancer, has been shown through genomic profiling studies to play a key role in Esophageal Cancer (EC). In this study, we performed the in-silico analysis of an RNA sequencing dataset to investigate the effects of omipalisib, a PI3K/mTOR inhibitor, on EC cell lines. Our objective was to identify novel molecular targets, particularly stress granule-related proteins, that contribute to drug resistance in EC. Using computational approaches including differential gene expression analysis, pathway analysis, and functional enrichment, we examined the transcriptomic changes in response to omipalisib treatment. Our analysis revealed downregulation of the PI3K/mTOR signaling pathway and upregulation of compensatory pathways such as FOXO and JAK-STAT signaling in response to omipalisib. Notably, we identified 16 stress granule-related proteins that were significantly upregulated, suggesting their potential role in drug resistance mechanisms. These findings provide new insights into the molecular mechanisms underlying drug resistance in EC and highlight potential novel targets for therapeutic intervention. Currently, EC is limited by the number of potential drugs for treatment, poor prognosis, and is prone to chemotherapeutic resistance to existing clinically proven drugs. Our computational analysis offers valuable insights into targeting stress granules for cancer drug discovery, potentially enhancing the development of new therapeutic strategies for EC. These results provide a strong foundation for future experimental validation and drug development efforts aimed at overcoming resistance to EC treatment. Received: 1 July 2024 | Revised: 20 September 2024 | Accepted: 20 November 2024 Conflicts of Interest The authors declare that they have no conflicts of interest to this work. Data Availability Statement The data that support the findings of this study are openly available in the NCBI Gene Expression Omnibus (GEO) database under accession number GSE143462 at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE143462. Author Contribution Statement Vinod Jangid: Conceptualization, Methodology, Software, Validation, Formal analysis, Data curation, Writing - original draft, Visualization. Chandrasekar Narayanan Rahul: Conceptualization, Methodology, Validation, Investigation,Writing - original draft. Aarthi Rashmi B: Validation, Writing - review & editing. Kanagaraj Sekar:Validation, Writing - review & editing, Supervision, Project administration.

Evaluating the impact of Xanthoparmelia conspersa extracts on signaling in HeLa cells and exploring their diverse biological activities

Xanthoparmelia conspersa is rich in specific secondary metabolites but an unexplored lichen species. This work determined the chemical composition and biological activities (anti-microbial, anti-protozoal, and cytotoxic) of its methanolic and hexane extracts. Additionally, we evaluated the potential of these extracts in modulating cancer signaling pathways in HeLa cells. The phytochemical analysis revealed that usnic acid was the predominant constituent in the hexane extract, while stictic acid was in the methanolic one. Among tested cell lines (VERO, FaDu, SCC-25, HeLa), cytotoxic selectivity was detected for X. conspersa hexane extract against the FaDu (SI 7.36) and HeLa (SI 2.19) cells. A noticeably better anti-microbial potential was found for hexane extract, however, the overall anti-microbial activity was relatively weak (28, 21, and 20% inhibition of Candida glabrata, Cryptococcus neoformans, and Escherichia coli, respectively). On the contrary, the anti-parasitic action of hexane extract was significant, with an IC50 value of 2.64 µg/mL against Leishmania donovani – amastigote and 7.18 µg/mL against Trypanosoma brucei. The detailed evaluation of the cancer-related signaling pathways in HeLa cells, done by two distinct methodologies (luciferase reporter tests), revealed that especially the hexane extract and usnic acid exhibited selective inhibition of Stat3, Smad, NF-κB, cMYC, and Notch pathways.

Circulating Micro-RNAs Predict the Risk of Recurrence in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a high tendency for developing a recurrent disease. Circulating micro-RNAs (cmiRNAs) obtained through liquid biopsy are potential prognostic biomarkers for the assessment of TNBC recurrence risk. In this study, we sequenced cmiRNAs from the serum samples of 14 recurrent and 19 non-recurrent TNBC cases and compared expression profiles in relation to recurrence status, survival data and miRNA expression in matched tumor samples. Differential expression analysis between recurrent and non-recurrent cases identified ten differentially expressed (DE) cmiRNAs, of which cmiRNAs miR-21-5p (p = 0.030, HR = 1.87, 95% CI 1.06-3.30), miR-16-5p (p = 0.032, HR = 0.53, 95% CI 0.30-0.95), and miR-26b-5p (p = 0.023, HR = 0.52, 95% CI 0.29-0.91) were associated with recurrence-free survival in multivariable survival analysis. Expression profiles of matched tumor and serum samples were shown to correlate with each other. DE cmiRNAs were associated with common cancer-related signaling pathways and improved the overall predictive performance of the logistic regression model assessing the recurrence risk. Our results indicate that recurrent and non-recurrent TNBC differ in their cmiRNA expression profiles, and that three specific cmiRNAs can be used to assess the risk of recurrence in TNBC.

Discovery of novel TANK-Binding Kinase 1 (TBK1) inhibitor against pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, underscoring the urgent need for developing new therapies. The upregulation of TBK1 activity plays a crucial role in multiple pancreatic cancer-related signaling pathways, suggesting that inhibiting the kinase activity of TBK1 could be a promising strategy. Herein, we discovered a novel TBK1 inhibitor, LIB3S0280, using a structure-based virtual screening (SBVS) strategy. In the anti-proliferative and viability assays, LIB3S0280 showed significant inhibition against pancreatic cancer cell lines that highly express TBK1 with the GI50 values of 2.24 and 4.71 μM and IC50 values of 6.64 and 10.98 μM at 96 h. For the downstream targets, LIB3S0280 can inhibit TBK1 downstream signaling by decreasing the phosphorylation of IκBα and AKT better than a known TBK1 inhibitor, BX-795. Furthermore, PDAC cells were arrested in G2/M and underwent apoptosis or senescence with the treatment of LIB3S0280. These findings suggest that TBK1 inhibitor LIB3S0280 has great potential as a lead compound in the further development of a novel treatment for PDAC.

CRISPR-based molecule-regulatory expression platform for specific immunotherapy of cancer.

Cancer is still a major challenge of human health. The abnormality of intracellular cancer-related signal pathways is an important mechanism for the occurrence of cancer. We used a molecular-senor to act on the endogenous signal molecules within the cell to redirect the abnormal signal flows in the cell to treat cancer. Based on CRISPR-dCas12f procedures, we combined aptamers and ribozymes to construct riboswitches, which served as molecular switches to reprogram sgRNAs, so that CRISPR-dCas12f redirected the intracellular anti-cancer signal flows after sensing specific input signal molecules. In addition, the activated molecular sensors and the inhibitory molecular sensors were constructed by combining transcription factors (VP64) and transcription inhibitors (KRAB) to specifically activate and inhibit target genes of interest. Our experimental results showed that the molecular sensors that we designed and constructed specifically sensed the endogenous signal molecules and then redirect the cancer related signal networks of cancer cells. In addition, corresponding logic gates were constructed to distinguish cancer cells from normal cells and redirect anticancer signal flows to trigger specific cancer immunotherapy. The constructed molecular sensors constructed specifically recognized the signal molecules within the cell and redirected the endogenous signal pathway to reprogram the fate of cancer cells.

Integrated microbiome and metabolome analysis reveals synergistic efficacy of basil polysaccharide and gefitinib in lung cancer through modulation of gut microbiota and fecal metabolites

Emerging evidence suggests that gut microbiota and its metabolites significantly influence the effectiveness of EGFR-TKIs (e.g., gefitinib, erlotinib) in lung cancer treatment. Plant polysaccharides can interact with gut microbiota, leading to changes in the host-microbe metabolome that may affect drug metabolism and therapeutic outcomes. Our previous research demonstrated the efficacy of basil polysaccharide (BPS) in treating various cancers by regulating hypoxic microenvironment and inhibiting epithelial-mesenchymal transition process. However, the potential impact of BPS on gut microbiota has not been thoroughly explored. In this study, we employed an immunodeficient gefitinib-resistant xenograft mouse model to explore whether BPS enhances the antitumor effects of gefitinib. A multi-omics approach, including 16S rDNA amplicon sequencing and LC-MS, was used to elucidate these synergistic effects. Our findings indicate that BPS can enhance tumor responsiveness to gefitinib by modulating the gut microbiota and its metabolites through multiple metabolic pathways. These changes in gut microbiota and metabolites could potentially affect cancer related signaling pathway and lung resistance-related protein, which are pivotal in determining the efficacy of EGFR-TKIs in cancer treatment.

Effects of BYL-719 (alpelisib) on human breast cancer stem cells to overcome drug resistance in human breast cancer.

Breast cancer continues to be a major health concern and is currently the most commonly diagnosed cancer worldwide. Relapse, metastasis, and therapy resistance are major clinical issues that doctors need to address. We believe BYL-719, which is PI3 kinase p110а inhibitor, could also inhibit the breast cancer stem cell phenotype and epithelial-to-mesenchymal transition (EMT). In addition to the PI3K/AKT signaling pathway, BYL-719 can also inhibit essential cancer-related signaling pathways, all of which would ultimately act on the microenvironment of cancer stem cells, which is quite complicated and regulates the characteristics of tumors. These include the stemness and resistance of malignant tumors, plasticity of cancer stem cells, and anti-apoptotic features. A three-dimensional (3D) mammosphere culture method was used in vitro to culture and collect breast cancer stem cells (BCSCs). MTT, clonogenic, and cell apoptosis assays were used to detect cell viability, self-renewal, and differentiation abilities. A sphere formation assay under 3D conditions was used to detect the mammophore inhibition rate of BYL-719. The subpopulation of CD44+CD24- was detected using flow cytometry analysis while EMT biomarkers and essential signaling pathways were detected using western blotting. All the data were analyzed using GraphPad Prism 9 software. BCSC-like cells were obtained by using the 3D cell culture method in vitro. We confirmed that BYL-719 could inhibit BCSC-like cell proliferation in 3D cultures and that the stemness characteristics of BCSC-like cells were inhibited. The PI3K/AKT/mTOR signaling pathway could be inhibited by BYL-719, and the Notch, JAK-STAT and MAPK/ERK signaling pathways which have crosstalk in the tumor microenvironment (TME) are also inhibited. By comparing eribulin-resistant breast cancer cell lines, we confirmed that BYL-719 could effectively overcome drug resistance. The 3D cell culture is a novel and highly effective method for enriching BCSCs in vitro. Furthermore, the stemness and EMT of BCSCs were inhibited by BYL-719 by acting on various signaling pathways. Finally, we believe that drug resistance can be overcome by targeting the BCSCs. Conjugation of BYL-719 with other anti-neoplastic agents may be a promising treatment for this in clinic.

Exploring Aspirin's Potential in Cancer Prevention: A Comprehensive Review of the Current Evidence.

Aspirin, traditionally recognized for its analgesic, anti-inflammatory, antipyretic, and antiplatelet effects, has recently attracted attention for its potential role in cancer prevention. Initially studied for cardiovascular disease prevention, emerging evidence suggests that aspirin may reduce the risk of certain cancers, particularly colorectal cancer (CRC). This narrative review integrates findings from early studies, animal models, epidemiological data, and clinical trials to evaluate aspirin's efficacy as a chemopreventive agent. Aspirin's anticancer effects are primarily attributed to its cyclooxygenase (COX) enzyme inhibition, which decreases prostaglandin E2 (PGE2) levels and disrupts cancer-related signaling pathways. While epidemiological studies support an association between aspirin use and reduced cancer incidence and mortality, especially for CRC and potentially for breast (BC) and prostate cancers (PCa), the risk of adverse effects, such as gastrointestinal (GI) and intracranial bleeding, complicates its use and warrants careful consideration. The decision to use aspirin for cancer prevention should be individualized, balancing its therapeutic benefits against potential adverse effects. It also underscores the necessity for further research to refine dosage guidelines, assess long-term impacts, and explore additional biomarkers to guide personalized cancer prevention strategies.

Predicting and Validating the Mechanism of Action of the Enema Formula in Treating Colorectal Cancer by Using Network Pharmacology, GEO, and TCGA Databases

Background: The GCF, created by Professor Liu Shenlin, an esteemed expert in traditional Chinese medicine, is rooted in principles to improve blood flow, relieve blood congestion, clear heat, and detoxify the body. Developed as an empirical formula, it holds significance in CRC treatment. Objective: This study aimed to predict and confirm the active elements, possible targets, and molecular mechanisms against colorectal cancer (CRC) in the GCF enema formula. Methods: Using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), we screened active elements and drug targets. Colorectal cancer (CRC)-related targets were collected from the Online Mendelian Inheritance in Man (OMIM) database, Disease Gene Network (DisGeNET) database, and Therapeutic Target Database (TTD). The overlap between action targets of all active elements and CRC-related targets was determined to find common targets. A Protein-Protein Interaction (PPI) network of common targets was built using the String database, and Cytoscape software was used for visual analysis to identify core targets. Simultaneously, the common targets were analyzed using the Metascape database for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Additionally, core targets and active elements were tested using Discovery Studio 2019 for molecular docking. Furthermore, the expression differences and prognostic impacts of core targets were examined across various cancer databases. Results: Screening revealed 90 active elements and 251 drug targets in the GCF. There were 6113 disease targets, with 113 common targets between CRC and the GCF. Core targets identified through PPI analysis included AKT1, STAT3, MYC, SRC, EGFR, and IL6. KEGG enrichment analysis uncovered 101 relevant pathways related to these targets. Molecular docking experiments confirmed favorable interactions between core targets and multiple active elements in the GCF. Additionally, examination of the Human Protein Atlas (HPA) database highlighted differential expression of core targets MYC and EGFR in normal colorectal tissue compared to CRC tissue. Conclusion: The GCF, comprising a combination of three drugs, appears to counteract CRC by influencing core targets, such as AKT1, STAT3, MYC, SRC, EGFR, and IL6. This process involves regulating multiple cancer-related signaling pathways, notably the PI3K-AKT pathway.

SCGB1A1 as a novel biomarker and promising therapeutic target for the management of HNSCC.

Head and neck cancer (HNC) is the sixth most common type of cancer worldwide, and head and neck squamous cell carcinoma (HNSCC) accounts for 90% of HNC cases. Furthermore, HNSCC accounts for 400,000 cancer-associated deaths worldwide each year. However, at present there is an absence of a versatile biomarker that can be used for diagnosis, prognosis evaluation and as a therapeutic target for HNSCC. In the present study, bioinformatics analysis was used to assess the relationship between hub genes and the clinical features of patients with HNSCC. The findings from the bioinformatics analysis were then verified using clinical samples and in vitro experiments. A total of 51 overlapping genes were identified from the intersection of differentially expressed genes and co-expressed genes. The top 10 hub genes were obtained from a protein-protein interaction network of overlapping genes. Among the hub genes, only secretoglobin family 1A member 1 (SCGB1A1) was significantly associated with both overall and disease-free survival. Specifically, upregulated SCGB1A1 expression levels were associated with prolonged overall and disease-free survival. Moreover, the SCGB1A1 expression levels were negatively correlated with drug sensitivity. Notably, it was demonstrated that SCGB1A1 was involved in tumor immunoreaction by affecting the infiltration of cells and checkpoint regulation of immune cells. Additionally, it was shown that SCGB1A1 regulated multiple key cancer-related signaling pathways, including extracellular matrix receptor interaction, transforming growth factor-β and tumor metabolism signaling pathways. Based on the results of the present study, SCGB1A1 may serve as a novel biomarker for predicting the diagnosis, prognosis and therapeutic effectiveness of certain drugs in patients with HNSCC. Moreover, SCGB1A1 may serve as a potential therapeutic target for the management of HNSCC.

“Thiophene”: A Sulphur Containing Heterocycle as a Privileged Scaffold

: In the rapidly expanding chemical realm of heterocyclic compounds with interesting therapeutic properties, the thiophene nucleus has established itself as a prospective entity. The biological activity of comparable substances produced via different pathways is of varying magnitudes. Medicinal chemists use their understanding of multiple synthetic pathways and the various physicochemical properties of such compounds to create a combinatorial library and conduct thorough searches for lead molecules. Due to their vast spectrum of biological actions, heterocyclic compounds play a crucial role in Medicinal chemistry and are extensively researched in the field of drug design and development. Thiophene, a sulfur- containing heterocyclic scaffold, has emerged as a rather well-explored scaffold for the synthesis of a library of molecules with biological functions, including antibacterial, antipsychotic, anticancer, analgesic, anti-inflammatory, anti-arrhythmic, and so on. Depending on the kind and position of substitution, thiophene analogues have been shown to bind to a wide spectrum of cancer-specific protein targets. As a result, thiophene analogues have been found to exert their biological effects by inhibiting various cancerrelated signalling pathways. The study of thiophene in Medicinal chemistry resulted in molecules that combine the thiophene moiety with traditional drug components in a single molecule. This review covers the biological and medical activity of compounds containing a thiophene nucleus, as well as information on thiophene behaviour, synthesis, and agents, with a focus on synthetic techniques, biological profiles, and structure-activity relationship (SAR) research.

Insights into the Anticancer Mechanisms Modulated by Gamma and Delta Tocotrienols in Colorectal Cancers.

Colorectal cancer (CRC) is a growing concern all over the world. There has been a concerted effort to identify natural bioactive compounds that can be used to prevent or overcome this condition. Tocotrienols (T3s) are a naturally occurring form of vitamin E known for various therapeutic effects, such as anticancer, antioxidant, neuroprotective, and anti-inflammatory activities. The literature evidence suggests that two T3 analogues, ie, gamma (γ)- and delta (δ)-T3, can modulate cancers via several cancer-related signaling pathways. The aim of this review was to compile and analyze the existing literature on the diverse anticancer mechanisms of γT3 and δT3 exhibited in CRC cells, to showcase the anticancer potential of T3s. Medline was searched for research articles on anticancer effects of γT3 and δT3 in CRC published in the past 2 decades. A total of 38 articles (26 cell-based, 9 animal studies, 2 randomized clinical trials, and 1 scoping review) that report anticancer effects of γT3 and δT3 in CRC were identified. The findings reported in those articles indicate that γT3 and δT3 inhibit the proliferation of CRC cells, induce cell cycle arrest and apoptosis, suppress metastasis, and produce synergistic anticancer effects when combined with well-established anticancer agents. There is preliminary evidence that shows that T3s affect telomerase functions and support anticancer immune responses. γT3 and δT3 have the potential for development as anticancer agents.

AB019. Detailed analysis of DNA hydroxymethylation observed with the malignant progression of IDH-mutant gliomas.

Gliomas vary in prognosis with World Health Organization (WHO) grade. Low-grade gliomas can undergo malignant progression (MP), becoming aggressive high-grade tumors, worsening prognosis. This is prevalent in isocitrate dehydrogenase-mutant (IDH-mt) gliomas like astrocytoma and oligodendroglioma, but the mechanism of MP is still not fully understood. High-grade IDH-mt gliomas have been reported to exhibit TET-mediated DNA hydroxymethylation, which is suggested to potentially influence gene expression. We hypothesized that hydroxymethylation in specific regions could be implicated in triggering MP. We collected glioma tumor samples over a decade, using WHO 2021 classification to study IDH-mt astrocytoma grade 2 progression to grades 3 or 4, indicating MP. Samples from five patients, demonstrating MP, were analyzed for DNA hydroxymethylation status across more than 850,000 genomic locations using the oxidative bisulfite process and Infinium EPIC methylation array. This was complemented by RNA sequencing for gene expression analysis and its correlation with hydroxymethylation, and motif-enrichment analysis to infer transcription factor involvement in hydroxymethylation-based gene regulation. Additionally, to delve into the fundamental causes of hydroxymethylation, we exposed an IDH-mt glioma cell line to hypoxic conditions and systematically explored the genomic locations where hydroxymethylation occurred. Our comprehensive analysis identified a significant overlap of hydroxymethylated genomic regions across samples during MP, with a notable enrichment in open sea and intergenic regions (P<0.001). These regions were significantly associated with cancer-related signalling pathways. Integration with RNA sequencing data revealed 91 genes with significant correlations between hydroxymethylation and gene expression, implying roles in cell cycle regulation and antineoplastic functions. Furthermore, motif-enrichment analysis suggested the potential regulatory role of KLF4 in these processes. The cell culture results revealed that a certain similarity exists between the hydroxymethylation patterns observed during MP and those in glioma cells cultured under hypoxic conditions. This study elucidates the importance of region-specific DNA hydroxymethylation in the MP of IDH-mt astrocytomas, suggesting its potential impact on gene expression relevant to cancer malignancy. Our findings propose a complex interplay between hydroxymethylation and gene regulation, which may offer new insights into the mechanisms driving glioma progression and highlight potential targets for therapeutic intervention.

Raddeanin A promotes the apoptosis of gastric cancer in conjunction with autophagy inhibitor Hydroxychloroquine via MAPK signaling pathway

PurposeGastric cancer (GC) is among the malignant cancers with the highest incidence and mortality worldwide. As GC is not very sensitive to current chemotherapy drugs, there is an urgent need to develop new effective drugs. Raddeanin A (RA) is extracted from the traditional Chinese medicine Anemone raddeana Regel, which has an anti-cancer effect. The purpose of this study was to explore the effects of RA on GC in vitro and in vivo. MethodsWe explored the targets of RA in GC through network pharmacology. MTT assay, flow cytometry, Western blotting, and other methods were used to detect the effects of RA on the proliferation, apoptosis, and autophagy of GC cells. After preconditioning with hydroxychloroquine (HCQ) and rapamycin, we observed the effects of RA-induced autophagy on apoptosis. We further verified the antitumor effect and safety of RA in vivo. Using SNU-1 xenograft tumor model in nude mice, tumor volume was observed and liver toxicity was observed by immunohistochemistry. ResultsMany cancer-related signaling pathways were visualized using Cytoscape software. Among them, the MAPK signaling pathway was one of the highest-ranked pathways. The MTT assay results suggested that RA could inhibit the proliferation of HGC-27 and SNU-1 cells effectively. Flow cytometry and Western blotting confirmed that RA could significantly induce apoptosis of HGC-27 and SNU-1 cells. Electron microscopy and Western blotting demonstrated that RA could induce autophagy of HGC-27 and SNU-1 cells. Further experiments suggested that HCQ, an autophagy inhibitor, could enhance the capacity of RA to induce apoptosis. In animal studies, we found that intraperitoneal injection of RA could effectively and safely inhibit gastric tumors. ConclusionsRA significantly inhibited the proliferation and induced autophagy and apoptosis of GC cells. In combination with HCQ, RA-induced apoptosis increased in vitro. The combined application of RA and autophagy inhibitors may serve as an added approach to the treatment of GC, but the underlying mechanism needs further exploration. In vivo, it was observed that RA has a good antitumor effect without increasing liver toxicity.