Colorectal Cancer Progression Research Articles

CYP24A1 DNA Methylation in Colorectal Cancer as Potential Prognostic and Predictive Markers.

The DNA methylation of CYP24A1 can regulate its gene expression and may play a role in the occurrence and progression of colorectal cancer (CRC). However, the association between CYP24A1 DNA methylation and the prognosis of CRC patients has not yet been reported. In this study, differential methylation analysis was conducted in both blood and tissue cohorts, and differential expression analysis was performed in the tissue cohort with in vitro validation. GO and KEGG enrichment analyses were performed on CYP24A1-related genes. A correlation between CYP24A1 promoter methylation and its gene expression was explored. Kaplan-Meier survival and Cox regression analyses were performed to investigate the impact of CYP24A1 DNA methylation on the prognosis of CRC patients. Prognostic risk scores were constructed for survival prediction. Immune infiltration analysis was also conducted. Our results showed that the hypermethylation of cg02712555 in tumor tissues (hazard ratio, 0.48; 95% confidence interval, 0.24-0.94; p = 0.032) and CpG site 41 in peripheral leukocytes (HR, 0.35; 95%CI, 0.14-0.84; p = 0.019) were both associated with decreased overall mortality in CRC patients. Prognostic risk scores showed robust predictive capabilities of these two CpG loci for the prognosis of CRC patients. CYP24A1 hypermethylation was positively correlated with infiltration levels of activated CD4 + T cells, activated CD8 + T cells, activated B cells, activated dendritic cells, and macrophages. Taken together, our findings indicate that the methylation levels of specific CpG sites within the CYP24A1 promoter region in blood leukocytes and tumors are potential prognostic and predictive markers for overall survival in CRC patients.

Soluble B7 and TNF family in colorectal cancer: Serum level, prognostic and treatment value.

Soluble immune checkpoints (sIC) are crucial factors in the immune system. They regulate immune responses by transforming intercellular signals via binding to their membrane-bound receptor or ligand. Moreover, soluble ICs are vital in immune regulation, cancer development, and prognosis. They can be identified and measured in various tumor microenvironments. Recently, sICs have become increasingly important in clinically assessing malignancies like colorectal cancer (CRC) patients. This review explores the evolving role of the soluble B7 family and soluble tumor necrosis factor (TNF) superfamily members in predicting disease progression, treatment response, and overall patient outcomes in CRC. We comprehensively analyze the diagnostic and prognostic potential of soluble immune checkpoints in CRC. Understanding the role of these soluble immune checkpoints in CRC management and their potential as targets for precision medicine approaches can be critical for improving outcomes for patients with colorectal cancer.

Cell Membrane-Integrated Neuroligin-1 Regulates the Anti-Inflammatory Effects of CRC Cell-Derived Exosomes.

Tumor-associated macrophages (TAMs) are one of the most abundant cell types in the colorectal cancer (CRC) tumor microenvironment (TME). CRC cell-derived exosomes support macrophage polarization toward an M2-like phenotype, which leads to tumor growth and metastasis. Neuroligin 1 (NLG1) is a transmembrane protein critical in synaptic function. We reported that NLG1 via an autocrine manner promotes CRC progression by modulating the APC/β-catenin pathway. This study aimed to answer whether NLG1 is involved in the exosome-mediated intercellular cross-talk between CRC and TAMs. Our results showed that exosomes of NLG1-expressing CRC cells induce M2-like (CD206high CD80low) polarization in macrophages. On the other hand, we found that the exosomes of the NLG1 knocked-down CRC cells reinforce the expression of CD80 and pro-inflammatory genes, including IL8, IL1β, and TNFα, in the macrophages, indicating an M1-like phenotype polarization. In conclusion, NLG1, as a cell-membrane-integrated protein, could be a therapeutic target on the surface of the CRC cells for developing clinical treatments to inhibit exosome-induced anti-inflammatory immune responses in TME.

RNA Modification and Digestive Tract Tumors: A Review.

Gastrointestinal tumors, including colorectal and liver cancer, are among the most prevalent and lethal solid tumors. These malignancies are characterized by worsening prognoses and increasing incidence rates. Traditional therapeutic approaches often prove ineffective. Recent advancements in high-throughput sequencing and sophisticated RNA modification detection technologies have uncovered numerous RNA chemical alterations significantly associated with the pathogenesis of various diseases, notably cancer. These discoveries have opened new avenues for therapeutic intervention. This article delves into epigenetic modifications, with a particular emphasis on RNA alterations such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), 1-methyladenosine (m1A), 7-methylguanosine (m7G), and N4-acetylcysteine (ac4C). It examines the functions and mechanisms of action of regulatory entities known as "Writers," "Readers," and "Erasers" to these modifications. Additionally, it outlines various methodologies for detecting these RNA modifications. Conventional techniques include radioactive isotope incorporation, two-dimensional thin-layer chromatography (2D-TLC), mass spectrometry, and immunological detection methods. Specialized methods such as bisulfite sequencing and reverse transcription stops are also discussed. Furthermore, the article underscores the significance of these modifications in the development, progression, and therapeutic targeting of gastrointestinal tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancers. This exploration provides foundational insights for enhancing diagnostic accuracy, treatment efficacy, and prognostic assessment in gastrointestinal oncology.

Genomic characterization of Escherichia coli with a polyketide synthase (pks) island isolated from ulcerative colitis patients

The E. coli strains harboring the polyketide synthase (pks) island encode the genotoxin colibactin, a secondary metabolite reported to have severe implications for human health and for the progression of colorectal cancer. The present study involves whole-genome-wide comparison and phylogenetic analysis of pks harboring E. coli isolates to gain insight into the distribution and evolution of these organisms. Fifteen E. coli strains isolated from patients with ulcerative colitis (UC) were sequenced, 13 of which harbored pks islands. In addition, 2,654 genomes from the public database were also screened for pks harboring E. coli genomes, 158 of which were pks-positive (pks+) isolates. Whole-genome-wide comparison and phylogenetic analysis revealed that 171 (158 + 13) pks+ isolates belonged to phylogroup B2, and most of the isolates belong to sequence types ST73 and ST95. One isolate from a UC patient was of the sequence type ST8303. The maximum likelihood tree based on the core genome of pks+ isolates revealed horizontal gene transfer across sequence types and serotypes. Virulome and resistome analyses revealed the0020preponderance of virulence genes and a reduced number of antimicrobial genes in pks+ isolates. This study significantly contributes to understanding the evolution of pks islands in E. coli.

Expression Pattern of AIFM3, VGLL4, and WNT4 in Patients with Different Stages of Colorectal Cancer.

Colorectal cancer (CRC) remains a significant health burden, and its delayed diagnosis at advanced stages leads to poor survival outcome. Detection of known and novel prognostic markers is essential. In this study, the status of likely prognostic markers-the apoptotic inducing factor (AIFM3), vestigial-like family member 4 (VGLL4), and WNT4-was evaluated. AIFM3, VGLL4, and WNT4 expression in CRC tissues across different stages (Dukes A-D) were analyzed using histological immunofluorescence staining and RNA sequencing analyses. In advanced CRC stages, progressive loss of normal crypt architecture, reduction of goblet cells, and necrotic debris were detected along with differential expression patterns of AIFM3, VGLL4, and WNT4. AIFM3 exhibited high reactivity in the lamina propria of healthy tissue and Dukes A, but this was diminished in advanced CRC stages. VGLL4 expression, initially confined to the lamina propria, increased significantly in the epithelium of Dukes B and C, with a cytoplasmic localization pattern. WNT4 expression was elevated in the CRC epithelium across all stages, contrasting with a significant reduction in lamina propria reactivity. RNA sequencing corroborated these findings, showing significant downregulation of AIFM3 and WNT4 and upregulation of VGLL4 in CRC tissues compared to controls. Expression of AIFM3 and WNT4 showed no correlation with survival outcome, while low VGLL4 expression was correlated with better survival outcome. The results suggest distinct roles for AIFM3, VGLL4, and WNT4 in CRC progression, highlighting only VGLL4 as a potential prognostic marker. Further evaluation of VGLL4 and its specific role in CRC progression remains to be elucidated.

A Novel Bacteriophage with the Potential to Inhibit Fusobacterium nucleatum-Induced Proliferation of Colorectal Cancer Cells.

Increasing evidence shows that Fusobacterium nucleatum (F. nucleatum) largely affects colorectal cancer (CRC) growth and progression; therefore, the inhibition of intratumoral F. nucleatum may be one realistic approach to combat CRC. Although antibiotics are helpful in eliminating bacteria, the major problem remains the rise of potential antibiotic-resistant strains and antibiotic-associated adverse effects. Currently, bacteriophage therapy has gained interest because of its high selectivity to bacterial hosts and may become a realistic approach in treating bacteria-associated cancers. In this study, a new F. nucleatum bacteriophage, ØTCUFN3, was isolated and its biological characteristics were identified. In vitro and in vivo studies were performed to investigate the effect of ØTCUFN3 in combating F. nucleatum-induced CRC growth. By applying ØTCUFN3 to F. nucleatum-induced CRC cell lines, p53+/+, and p53-/- isogenic HCT116 cells, our results revealed an inhibition of CRC proliferation and the expression of epithelial-to-mesenchymal transition (EMT) markers. ØTCUFN3 injection also reduced the growth of F. nucleatum-induced mouse xenografts. Our results demonstrated the use of F. nucleatum bacteriophage against CRC, laying the foundation for the future usage of bacteriophage in cancer treatment.

LGALS4 inhibits glycolysis and promotes apoptosis of colorectal cancer cells via β‑catenin signaling.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Glycolysis serves a crucial role in the development of CRC. The aim of the present study was to investigate the function of lectin galactoside-binding soluble 4 (LGALS4) in the regulation of glycolysis and its therapeutic potential in CRC. In the present study, 175 overlapping differentially expressed genes were identified by comprehensive analysis of The Cancer Genome Atlas database and the GSE26571 CRC dataset from the Gene Expression Omnibus database. LGALS4 was identified as the central gene by prognostic analysis using the mimetic map construction method and least absolute shrinkage and selection operator Cox regression. In vitro experiments were performed to evaluate the effects of LGALS4 overexpression on CRC cell phenotype and aerobic glycolysis, as well as its relationship with β-catenin signaling. LGALS4 was significantly downregulated in CRC, with an average 3-fold decrease compared with LGALS4 expression levels in normal tissues. LGALS4 was also significantly associated with patient survival. LGALS4 overexpression inhibited CRC cell growth, induced cell cycle arrest and enhanced 5-fluorouracil (5-FU)-induced apoptosis. Specifically, LGALS4 overexpression resulted in a ~50% decrease in cell proliferation and a ~2-fold increase in apoptosis. In addition, LGALS4 overexpression inhibited aerobic glycolysis and reduced glucose-dependent and glycolytic activity in CRC cells. The downregulatory effect of LGALS4 on glycolysis-related genes was further enhanced by the addition of the β-catenin inhibitor XAV-939. LGALS4 expression decreased CRC progression by inhibiting glycolysis and affecting β-catenin signaling. Overexpression of LGALS4 reduced the proliferation and glycolytic capacity of CRC cells and also enhanced their sensitivity to 5-FU. These results may potentially provide new perspectives for CRC treatment and targets for future clinical intervention strategies.

Chemokine family significance and prognostic value in colorectal cancer.

Colorectal cancer (CRC) poses a substantial global health concern, exhibits inconspicuous early symptoms, and is typically diagnosed at advanced stages leading to unfavorable outcomes. The intricate tumor microenvironment plays a crucial role in CRC development and progression, where chemokines contribute significantly. These chemokines exhibit widespread expression within tumor cells, facilitating immune cell infiltration, angiogenesis, and the establishment of distant metastases. The dysregulation of various chemokines in the context of CRC has emerged as a pivotal factor in the disease's pathogenesis. To explore the relationship between chemokine gene expression and CRC patient survival, as well as to clarify their biological roles,We conducted RNA-sequencing (RNA-seq) analysis on a cohort of 88 CRC patients with tumor samples, thereby enabling a detailed exploration of chemokine involvement in CRC. This study was rigorously augmented using comprehensive datasets from The Cancer Genome Atlas (TCGA), ensuring a robust analysis of gene expression patterns associated with clinical outcomes. Through data analysis, we identified key genes from the chemokine family thought pertinent to CRC outcomes. Consequently, we constructed a novel prognostic model based on the risk score derived from these chemokine expressions. Validation against clinical metadata, executed through immunohistochemistry analysis, affirmed the relevance and accuracy of our model in predicting patient survival. Our findings illuminate the critical role of chemokines in shaping the immune microenvironment of CRC, thereby highlighting potential therapeutic targets for future treatment strategies. Our new prognostic model could provide important information for the development of targeted therapies for CRC, enhancing personalized treatment approaches andultimately improving survival for CRC patients.

Glycosphingolipids-Dependent Phospholipid Metabolism Enhances Cancer Initiation and Progression through SMPD1/GLTP/B3GALT4/ST8SIA6 Signaling Axis: A Novel Therapeutic Target.

Colorectal cancer (CRC) is a prevalent malignancy with high morbidity and mortality rates globally. Advances in single-cell sequencing technology have enabled comprehensive analyses of tumor cells at single-cell resolution, providing valuable insights into the molecular mechanisms underlying CRC initiation and progression. In this study, we integrated single-cell sequencing data with the TCGA database to identify key molecular pathways involved in CRC pathogenesis. Our analysis revealed that dysregulation of phospholipid metabolism, particularly sphingolipid metabolism, plays a crucial role in CRC development. Specifically, we observed aberrant expression of genes involved in sphingolipid biosynthesis and degradation, as well as altered levels of various sphingolipid metabolites in CRC cells. Furthermore, we identified several potential therapeutic targets, including SMPD1, GLTP, B3GALT4, and ST8SIA6, within the sphingolipid metabolism pathway that could be exploited for the development of novel CRC treatments. Overall, our findings provide novel insights into the molecular mechanisms underlying CRC and highlight the importance of targeting phospholipid metabolism, specifically sphingolipid metabolism, as a potential therapeutic strategy for CRC.

Targeting KAT7 inhibits the progression of colorectal cancer.

Rationale: Colorectal cancer (CRC) is a leading cause of cancer-related mortality. Epigenetic modifications play a significant role in the progression of CRC. KAT7, a histone acetyltransferase, has an unclear role in CRC. Methods: In this research, we analyzed the expression of KAT7 in CRC patients and its correlation with prognosis using the GEO database, western blot, and immunohistochemistry. We assessed the impact of KAT7 on CRC cell functions through cell viability, colony formation, flow cytometry, scratch, and transwell assays. Mechanistic insights were obtained via RNA sequencing and ChIP-qPCR. Additionally, we evaluated the effects of KAT7 on CRC growth and metastasis in vivo using mouse subcutaneous tumor and lung metastasis models. Results: In this study, we discovered an upregulated KAT7 signaling pathway in CRC and its association with poor patient survival. Knockdown of KAT7 promotes apoptosis and inhibits proliferation, migration, and invasion of CRC cells. Conversely, KAT7 overexpression enhanced these cellular processes. In vivo assays confirmed that knockdown of KAT7 can inhibit CRC proliferation and lung metastasis. Mechanistically, KAT7 acetylated histone H3 at lysine 14 (H3K14) to enhance MRAS transcription, which activated the MAPK/ERK pathway and promoted tumorigenesis. The enzymatic function of KAT7 as an acetyltransferase is crucial for the advancement of colorectal cancer. In KAT7 knockdown CRC cells, re-expression of KAT7, but not an acetyltransferase-deficient mutant, rescued MRAS expression, ERK phosphorylation, and CRC tumorigenesis. Conclusion: We found that KAT7 is highly expressed in CRC patients, and those with high KAT7 expression have a worse prognosis. KAT7 enhances MRAS gene transcription by promoting H3K14 acetylation, thereby activating the MAPK/ERK pathway and promoting malignant phenotypes of CRC. In summary, KAT7 represents a promising target for CRC therapy.

Exploring the role of Bisphenol A in obesity-driven colorectal cancer progression: network toxicology and multi-organ pathology in animal models.

Bisphenol A (BPA), an endocrine disruptor, is linked to cancer progression in estrogen-responsive tissues, but its role in promoting colorectal cancer (CRC) progression in the context of obesity remains underexplored. This study examines BPA's influence on CRC in obese Sprague-Dawley rats using network toxicology and experimental models. Computational analysis using the Database for Annotation, Visualization, and Integrated Discovery identified pathways such as "CRC" and "chemical carcinogenesis-receptor activation", implicating the PI3K-AKT pathway in IL-1 beta upregulation and BPA's role in CRC during obesity. Thirty male rats were grouped (n = 6) as follows: N (normal diet), NC (normal diet + CRC), HC (high-fat diet + CRC), NCB (normal diet + CRC + BPA), and HCB (high-fat diet + CRC + BPA). CRC was induced with 1,2-dimethylhydrazine (40 mg/kg), and BPA (25 mg/kg) was administered for 19 weeks. Although BPA exposure did not affect body weight or biochemical parameters, the HCB group exhibited significant histopathological changes in the colon, including lymphoid hyperplasia, liver damage, and increased IL-1β levels. Furthermore, diet influenced adipocyte size, exacerbating BPA's effects on CRC progression. Findings suggest BPA may worsen CRC progression in obese rats through identified pathways, promoting multi-organ pathology and underscoring the need for stricter regulations, especially for vulnerable populations. ENVIRONMENTAL IMPLICATION: Bisphenol A (BPA), a widespread environmental contaminant, is increasingly linked to serious health issues, including cancer, in susceptible populations. Our study highlights BPA's role in promoting obesity-driven colorectal cancer (CRC) progression, demonstrating its carcinogenic potential in high-risk contexts. These findings emphasize the urgent need for regulatory scrutiny of BPA exposure, particularly in obese individuals, and support the development of safer alternatives. Addressing BPA's impact can contribute to preventive health strategies and inform policies aimed at reducing environmental and public health risks associated with endocrine-disrupting chemicals.

DNA methylation-induced suppression of PRDM16 in colorectal cancer metastasis through the PPARγ/EMT pathway.

PR/SET domain 16 (PRDM16) is an important transcription factor in the differentiation process of brown adipocytes, which plays an important role in maintaining the special morphological characteristics and cellular function of brown adipocytes. However, the role of PRDM16 in human colorectal cancer (CRC) is currently unknown. Methylation sequencing, methylation-specific PCR (MSP), multiple bioinformatics analyses, Co-Immunoprecipitation (Co-IP) assay and Immunofluorescence (IF) staining, in vitro and in vivo functional experiments were performed to study the biological role of PRDM16 in CRC progression. Our study found that methylation level of PRDM16 was associated with CRC and lung metastasis of CRC by DNA methylation sequencing. Furthermore, we identified methylation sites within the promoter region of PRDM16. PRDM16 expression was significantly lower in human CRC tissue samples and dramatically associated with tumor size, T stage, overall survival rates and disease-free survival rates of CRC patients. Down-regulation of PRDM16 significantly promoted proliferation, migration, and invasion of CRC cells by regulating EMT pathway in vitro and in vivo. Decitabine which was a methylate inhibitor increased PRDM16 expression and inhibited CRC progression in vitro and in vivo. Further study showed that PRDM16 interacted with PPAR γ in nucleus and upregulated its expression in CRC. PPAR γ expression was lower in CRC tissues compared with the adjacent colorectal mucosal tissues. PPAR γ suppressed CRC progression including proliferation, colony formation, migration and invasion via EMT pathway, but not affect PRDM16 expression. Decitabine treatment could reverse the biological effects caused by PPAR γ down-regulation in CRC cells. Our study first shows that DNA methylation-mediated suppresser role of PRDM16 in CRC progression via PPAR γ/EMT pathway.

A Comparison of International Modelling Methods to Evaluate Health Economics of Colorectal Cancer Screening: A Systematic Review.

Cost-effectiveness analysis (CEA) is an accepted approach to evaluate cancer screening programmes. CEA estimates partially depend on modelling methods and assumptions used. Understanding common practice when modelling cancer relies on complete, accessible descriptions of prior work. This review's objective is to comprehensively examine published CEA modelling methods employed to evaluate Colorectal Cancer (CRC) screening from an aspiring modeller's perspective. It compares existing models highlighting the importance of precise modelling method descriptions, and essential factors when modelling CRC progression. MEDLINE, EMBASE, Web of Science and Scopus electronic databases were used. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement and data items from previous systematic reviews formed a template to extract relevant data. Specific focus included model type, natural history, appropriate data sources and survival analysis. Seventy-eight studies, with 52 unique models found. Twelve previously published models were reported in 39 studies, with 39 newly developed models. CRC progression from the onset was commonly modelled, with only six models not including it as a model component. Modelling methods needed to simulate CRC progression depend on the natural history structure and research requirements. For aspiring modellers, accompanying models with clear overviews and extensive modelling assumption descriptions is beneficial. Open-source modelling would also allow model replicability and result in appropriate decisions suggested for CRC screening programmes.

Regulation of NLRP3/TRIM family signaling in gut inflammation and colorectal cancer.

CRC (Colorectal cancer) ranks among the most prevalent tumors in humans and remains a leading cause of cancer-related mortality worldwide. Numerous studies have highlighted the connection between inflammasome over-activation and the initiation and progression of CRC. The activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome is dependent on the nuclear NF-kβ (Nuclear Factor kappa-light-chain-enhancer of activated B cells) pathway, leading to the maturation and release of inflammatory cytokines such as IL-1ß (Interleukin 1 beta) and IL-18 (Interleukin 18). While inflammation is crucial for defense mechanisms and tissue repair, excessive information can pose significant risks. Mounting evidence suggests that overactivation of the inflammasome contributes to the pathogenesis of inflammatory diseases. Consequently, there is a concerted effort to tightly regulate inflammasome activity and mitigate excessive inflammatory responses, particularly in conditions such as IBD (Inflammatory Bowel Disease), which includes Ulcerative Colitis and Crohn's Disease. The tripartite motif (TRIM) protein family, characterized by a conserved structure and rapid evolutionary diversification, includes members with critical roles in ubiquitination and other regulatory functions. Their importance in modulating inflammatory responses is widely acknowledged. This article aims to investigate the interplay between TRIM proteins and the NLRP3 Inflammasome in CRC and gut inflammation, offering insights for future research endeavors and potential therapeutic strategies.

MiR-424-5p Promotes Proliferation, Migration and Invasion of Colorectal Cancer Cells via the Targeting TXNIP/Hippo Axi.

Aggressive biological behavior leads to unfavorable survival of colorectal cancer (CRC) patients. Dysregulation of TXNIP has been reported to be associated with the occurrence, proliferation and metastasis of malignancies such as liver cancer, lung cancer, kidney cancer, gastric cancer, and pancreatic cancer. MiR-424-5p has been reported as a negative regulator of TXNIP involved in lipopolysaccharide-induced acute kidney injury. And disordered Hippo pathway and YAP/TAZ-TEAD activity are related to tumor progression. The study was designed to clarify the function of miR-424-5p and thioredoxin interacting protein (TXNIP) in the progression of CRC. The expression pattern of TXNIP and miR-424-5p was detected by immunohistochemistry, qRT-PCR and/or Western blotting. CCK-8 assays and transwell assays were applied to investigate the effect of TXNIP and miR-424-5p on cell proliferation, invasion and migration. Luciferase reporter assays were used to verify the transcriptional regulation among TXNIP, miR-424-5p and Hippo signaling pathway. TXNIP was poorly expressed whereas miR-424-5p was highly expressed in CRC tissues and cells. TXNIP overexpression suppressed proliferation, invasion and migration of CRC cells. It also suppressed the malignant behavior of the CRC cells promoted by miR-424-5p. Mechanically, TXNIP overexpression significantly inhibited YAP/TAZ transcriptional activity, and the highly expressed miR-424-5p in CRC targeted TXNIP mRNA. The study clarify a novel miR-424-5p/TXNIP/Hippo signaling pathway that facilitated CRC cells proliferation, migration and invasion. The above findings suggested that miR-424-5p and TXNIP might serve as the potential therapeutic targets for CRC patients.

FOXS1, frequently inactivated by promoter methylation, inhibited colorectal cancer cell growth by promoting TGFBI degradation through autophagy-lysosome pathway.

Tumor suppressor gene (TSG) inactivation by epigenetic modifications contributes to the carcinogenesis and progression of colorectal cancer (CRC). Expression profiling and CpG methylomics revealed that a forkhead-box transcriptional factor, FOXS1, is downregulated and methylated in CRC. To assess the biological functions and underlying mechanisms of FOXS1 in colorectal cancer. Public databases, semi-quantitative RT-PCR, immunohistochemistry, MSP, and BGS were used to analyze FOXS1 expression and promoter methylation in CRC. Stable FOXS1-overexpressing or knockdown cell lines were established. Cell growth, colony formation, flow cytometry, GFP-LC3 puncta detection, Ad-mCherry-GFP-LC3B, qPCR, in vivo subcutaneous tumor model, RNA-seq, western blotting, immunofluorescence, Co-IP assays, and protein stability analysis were performed to investigate the underlying molecular mechanisms of FOXS1. In CRC, FOXS1 was frequently downregulated due to promoter CpG methylation, acting as an independent prognostic marker. Moreover, FOXS1 exerts inhibitory effects on the growth of CRC cells in vitro and in vivo, while concurrently promoting CRC cell autophagy. Intriguingly, we found that FOXS1 interacted with transforming growth factor beta induced (TGFBI) and FOXS1 promoted TGFBI degradation through the autophagy-lysosome pathway rather than the ubiquitin-proteasome system. FOXS1 was also found to facilitate the interaction between TGFBI and lysosomal associated membrane protein 2A (LAMP2A), leading to the translocation of TGFBI into lysosomes for degradation. Additionally, FOXS1 regulates AKT phosphorylation and FOXO3a nuclear translocation, promoting the transcription of autophagy-related genes downstream of FOXO3a. Restoration of TGFBI expression reversed the suppressive effect exerted by FOXS1 on the growth of colorectal cancer cells. FOXS1 functions as a tumor suppressor that is methylated in CRC and promotes the lysosomal degradation of TGFBI, regulates cell growth and promotes autophagy in CRC through the TGFBI/AKT/FOXO3a signaling pathway. These findings indicate that FOXS1 exhibits potential as a promising biomarker and therapeutic target for colorectal cancer.

FBXW7 metabolic reprogramming inhibits the development of colon cancer by down-regulating the activity of arginine/mToR pathways.

FBXW7 is a tumor suppressor gene that regulates metabolism and is associated with the onset and progression of colorectal cancer (CRC)), however, the precise mechanism whereby FBXW7 participates in the metabolic reprogramming of CRC remains unclear. Here, the research aims to reveal the association between the expression of FBXW7 and clinical variables and to investigate the molecular mechanism by which FBXW7 plays a critical role in the development of CRC. The clinical importance of FBXW7 in CRC was determined by immunohistochemistry. Non-targeted metabolomics was utilized to explore the role of FBXW7 in the metabolic regulation of CRC. Low expression of FBXW7 was associated with poor prognosis in individuals with CRC, both at the mRNA and protein levels. FBXW7 over-expression inhibited CRC cell growth, colony formation, migration, and invasion. Non-targeted metabolomics unveiled that FBXW7 over-expression directly caused the deprivation of arginine which led to downmodulation of mTOR signaling pathway; meanwhile, FBXW7-related metabolites were primarily concentrated in the mTOR signaling pathway. In summary, the research identified a novel mechanism of action of FBXW7 in CRC. The research findings provide a theoretical foundation for the prognostic prediction and therapeutic planning of CRC based on metabolic reprogramming.

Glycyrrhizic acid reduces neutrophil extracellular trap formation to ameliorate colitis-associated colorectal cancer by inhibiting peptidylarginine deiminase 4.

In traditional Chinese medicine, the radices of Glycyrrhiza uralensis Fisch., known as liquorice, have been used for relieving cough, alleviating pain and harmonizing the actions of all medicinals in a formula. Glycyrrhizic acid (GA), a natural compound derived from licorice, exhibits notable anti-inflammatory properties. Neutrophil extracellular trap (NET) generated by peptidylarginine deiminase 4 (PAD4) has been implicated in the progression of colitis to colitis-associated colorectal cancer (CAC). This study aims to investigate whether GA can ameliorate CAC through the inhibition of PAD4 activity and reduction of NET formation. We investigated the correlation between PAD4 expression levels and immune cell infiltration in colorectal cancer utilizing the TIMER database, while also assessing PAD4 levels and activity in human CAC biopsy samples. To evaluate the therapeutic potential of licorice acid on CAC in vivo, we employed the AOM/DSS model and confirmed its inhibitory effects on NET formation in vitro. Furthermore, we explored whether licorice acid can restore immune cell cytotoxicity by diminishing NET formation through fluorescence transfection of CT26cell lines and subsequent sorting of CD8+ T cells. Additionally, we elucidated the detrimental role of PAD4 in CAC progression using PAD4-/- mice. We observed that GA ameliorated colonic inflammation, reduced tumorigenicity, and decreased NET formation, as evidenced by decreased levels of PAD4, citH3, MPO and MMP-9. In vitro experiments demonstrated that GA effectively bound to PAD4 and inhibited its enzyme activity. Furthermore, GA prevented epithelial cell destruction while enhancing CD8+ T-cell-mediated tumor killing through the suppression of NET formation in a coculture system. We demonstrate that GA inhibits CAC occurrence by suppressing PAD4 activity and reducing NET formation.

Innovative approaches in colorectal cancer screening: advances in detection methods and the role of artificial intelligence.

Colorectal cancer (CRC) is the third most prevalent cancer globally and poses a significant health threat, making early detection crucial. This review paper explored emerging detection methods for early screening of CRC, including gut microbiota, metabolites, genetic markers, and artificial intelligence (AI)-based technologies. Current screening methods have their respective advantages and limitations, particularly in detecting precursors. First, the importance of the gut microbiome in CRC progression is discussed, highlighting how specific microbial alterations can serve as biomarkers for early detection, potentially enhancing diagnostic accuracy when combined with traditional screening methods. Next, research on metabolic reprogramming illustrates the relationship between metabolic changes and CRC, with studies developing metabolite-based detection models that show good sensitivity for early diagnosis. In terms of genetic markers, methylated DNA markers like SEPTIN9 have demonstrated high sensitivity, although further validation across diverse populations is necessary. Lastly, AI technology has shown immense potential in improving adenoma detection rates, significantly enhancing the quality of colonoscopic examinations through image recognition techniques. This review aims to provide a comprehensive perspective on new strategies for CRC screening, emphasizing the potential of noninvasive detection technologies and the prospects of AI and genomics in clinical applications. Despite several challenges, this review advocates for future large-scale prospective studies to validate the effectiveness and cost-effectiveness of these new screening methods while promoting the implementation of screening protocols tailored to individual characteristics.