Colorectal cancer(CRC) is one of the most common malignant tumors of the digestive system, and Traditional Chinese Medicine has shown good efficacy in its treatment and prognosis. Wumei Wan(WMW) is widely used in the treatment of digestive system and tumor diseases, with effects such as anti-diarrheal, anti-dysentery, and pain relief. Modern pharmacological studies suggest that its active ingredients have anti-inflammatory, antioxidant, and anti-tumor properties. However, there is still a lack of systematic research on the role of WMW in the prevention and treatment of CRC and its molecular mechanisms. The aim of this study is to clarify the key active components and primary mechanisms by which WMW inhibits the initiation and progression of CRC, utilizing a multi-faceted approach including chemical composition analysis, network pharmacology, multi-omics studies, molecular biology validation, and molecular simulations. UHPLC-HRMS/MS was used to identify the chemical components in WMW decoction and post-administration serum, and network pharmacology analysis was combined to predict potential targets and signaling pathways. Key differential pathways were selected through combined transcriptomics and proteomics analysis, and the expression patterns of the FAK/Src/YAP axis in CRC were verified using the GEO database. An azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CRC mouse model was constructed to assess the effects of WMW on survival rate, tumor burden, histological changes in the colon, and the expression of related proteins. The expression of downstream genes CTGF and Axin2 was detected via qRT-PCR, and the regulatory effects of WMW-containing serum on FAK/Src/YAP signaling were examined in the HCT116cells model. Finally, molecular docking and molecular dynamics simulations were performed. UHPLC-HRMS/MS analysis identified 15 circulating components of WMW following administration. Network pharmacology analysis revealed 241 overlapping targets between WMW-related targets and CRC-associated genes, which were enriched in pathways related to inflammation regulation, cell proliferation, and focal adhesions, with FAK/Src/YAP-related signaling features emerging as a central network module. In the AOM/DSS-induced CRC model, WMW treatment was associated with changes in body weight, tumor burden, and colonic mucosal structure, along with reduced tissue expression levels of VEGF and p53. Multi-omics analyses showed coordinated alterations in pathways related to inflammation, proliferation, and extracellular matrix (ECM) remodeling following WMW intervention. Analysis of GEO datasets confirmed elevated expression of PTK2, Src, and YAP1 in CRC tissues, supporting aberrant focal adhesion-YAP-associated signaling features in clinical CRC. In vivo and in vitro experiments showed that WMW intervention was associated with reduced phosphorylation levels of FAK, Src, and YAP, decreased stress fiber formation, attenuated YAP nuclear localization, and lower expression of CTGF and PCNA. Molecular docking and molecular dynamics simulations indicated that several circulating components could stably interact with the FAK kinase domain, with auraptene exhibiting relatively favorable binding characteristics. These findings suggest that WMW intervention is associated with coordinated alterations in inflammation-related signaling, cell proliferation, and extracellular matrix remodeling in CRC, with focal adhesion-YAP-related mechanotransduction representing a potential associated feature. This study provides integrated experimental evidence supporting further investigation of WMW and traditional Chinese medicine-based strategies targeting focal adhesion-associated signaling in CRC research.

The regulation of gene expression and its connection to the dynamics of plasma membrane signaling hubs (lipid rafts) have largely remained unexplored to date. Ras signaling plays crucial roles in the initiation and progression of colon adenocarcinoma (COAD) by regulation of gene expression, including DNA methyltransferase 1 (DNMT1). Gene-specific hypermethylation and genome-wide hypomethylation are well characterized in various cancers, including COAD. In view of this, we have examined how the signaling pathway orchestrated by plasma membrane-associated lipid rafts coordinates with the epigenetic modifications that precisely modulate a specific group of (hub) genes involved. First, we have identified COAD-specific hub genes (COL1A1, COL1A2, COL4A1, SPP1, SPARC, and THBS2) through extensive bioinformatics analyses, which revealed that increased expression of these hub genes facilitates the onset and progression of COAD. Comprehensive computational analyses of methylation patterns confirmed that atypical hypomethylation at these gene loci elevates their expression in COAD. Thereafter, we have explored how the dynamics of plasma membrane signaling hubs', such as lipid rafts, influence gene-specific promoter methylation dynamics within the nucleus of COAD cells. Our experimental analyses indicated that the transient destabilization (TD) of lipid rafts through ectopic cholesterol efflux activates the epidermal growth factor (EGF)-independent lipid raft-associated epidermal growth factor receptor (EGFR)-rat sarcoma (RAS)-mitogen-activated protein kinase (MAPK) signaling pathway, leading to increased expression of DNMTs and decreased expression of hub genes in COAD cells. These results strongly suggest that the plasma membrane lipid raft-associated EGFR-RAS-MAPK axis, functioning from membrane signaling hubs, can regulate genes located in various chromosomal locations. Ectopic expressions of DNMT1 impose an epigenetic checkpoint at those target loci by methylation of promoter DNA of the respective genes. We conclude that, gene specific hypomethylation of some genes, including COL1A1, COL1A2, COL4A1, SPP1, SPARC, and THBS2 drives COAD and would serve as potential markers for COAD screening.

The clinical efficacy of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) remains limited. Modulation of the glucagon-like peptide-1 receptor (GLP-1R) may enhance T-cell-mediated antitumor responses. The present study aimed to evaluate the antitumor effects of the GLP-1R antagonist Exendin 9-39 (Exe-9) combined with anti-programmed cell death protein-1 (PD-1) treatment in preclinical CRC models. Using in vitro co-culture assays, ELISA and in vivo murine models, alongside immunohistochemical and molecular analyses of clinical samples, HT-29 and MC38-OVA colon cancer cell lines were co-cultured in vitro with activated T cells in the presence of Exe-9. In vivo, male BALB/c mice were injected with MC38 to establish a CRC model and nude mice were used to assess T-cell dependency. To evaluate this synergistic effect, BALB/c mice with CRC were treated with Exe-9, anti-PD-1 or a combination. Additionally, clinical CRC samples were analyzed to assess the association of GLP-1R expression with the immunotherapy response. Exe-9 significantly enhanced T-cell-mediated cytotoxicity in CRC cell lines and reduced tumor growth in immunocompetent CRC mice; however, this effect was not observed in nude mice. Furthermore, combination therapy with the GLP-1R antagonist and anti-PD-1 yielded an improved antitumor effect compared with either treatment alone, and high GLP-1R ex2pression in clinical samples correlated with poor ICI response. These findings suggest that GLP-1R antagonism potentiates T-cell-mediated antitumor immunity and may provide a promising adjunctive therapeutic strategy for patients with CRC when combined with ICIs in the future.

The VAX2-SERPINE1 axis modulates colorectal cancer cell proliferation and apoptosis through WNT/beta-catenin signaling.

Trastuzumab deruxtecan in non-breast solid tumors: Expanding indications, efficacy, and future directions.

Context-specific roles of DDX60 in colorectal cancer via autophagy regulation and DDX58 signaling.

ITLN1 suppresses colorectal cancer progression by inhibiting Wnt/β-catenin-mediated EMT and reprogramming macrophage polarization.

PLCγ1 in curdione-mediated angiogenesis-EMT interaction and colorectal cancer metastasis.

Colorectal cancer (CRC) is the third most common cancer globally and a major contributor to cancer-related mortality. Implementation of screening programs in average-risk populations have reduced CRC-related mortality, despite the suboptimal sensitivity of currently used techniques. Novel screening methods with improved accuracy would be expected to further reduce CRC mortality. We previously developed a surface plasmon resonance-based assay that utilizes a N-glycolyl neuraminic acid (Neu5Gc)-specific lectin, SubB2M, to measure levels of Neu5Gc glycoconjugate cancer biomarkers in human serum. In this study, Neu5Gc glycoconjugate levels were measured in the serum of colorectal cancer patients (n = 96) and compared to cancer-free controls (n = 24). A significant increase in serum Neu5Gc levels was observed in patients at every stage of colorectal cancer when compared to the cancer-free control group (P ≤ 0.001). Receiver operating characteristic analysis of these data showed that the assay could distinguish colorectal cancer cases from healthy controls with a sensitivity of 93.75% and specificity of 79.17% and had an AUC of 0.8529. These findings reveal a correlation between serum Neu5Gc and colorectal cancer and highlight the potential for Neu5Gc glycoconjugates to be used as a serum biomarker for colorectal cancer.

Traditional Chinese medicine (TCM) has demonstrated multiple therapeutic advantages in colorectal cancer (CRC) management. The herbal formula Fuzheng Shengbai Decoction (FZSB) has been widely used in clinical practice with well-documented therapeutic efficacy; nevertheless, the mechanisms underlying its anti-CRC effects remain largely unexplored. To evaluate the therapeutic efficacy of FZSB in colorectal cancer and its potential underlying mechanisms. Through both clinical and experimental studies, the therapeutic efficacy and underlying mechanisms of FZSB in colorectal cancer were investigated. A clinical cohort of postoperative CRC patients and BALB/c mouse xenograft models were used to evaluate its immunomodulatory and antitumor effects. RIP-qPCR, MeRIP-qPCR, and MeRIP-seq were employed to explore the potential molecular mechanisms of FZSB. Molecular docking was performed to assess the interactions between active components of FZSB and key targets. FZSB significantly inhibited CRC growth and proliferation both in vivo and in vitro. In the clinical cohort, FZSB elevated the CD4+/CD8+ T-cell ratio. In xenograft models, FZSB increased CD8+ T-cell infiltration, proportion, and activation, and upregulated the tumor suppressor CLCA2, which was positively correlated with prognosis. Mechanistically, FZSB stabilized YTHDC2, promoting m6A-dependent CLCA2 mRNA stabilization and expression. Molecular docking indicated that multiple FZSB bioactive compounds could interact favorably with YTHDC2 and CLCA2. FZSB enhances anti-colorectal cancer immune responses and is associated with increased CD8+ T-cell activation, while concurrently modulating the YTHDC2-CLCA2 axis via m6A -mediated mRNA stabilization.

The current paper describes the protocol for the Hybrid type 1 effectiveness-implementation trial titled Multilevel Action Toward Colorectal Cancer and Hepatitis C Education and Screening (MATCHES). The aims of the MATCHES intervention trial are to promote both colorectal cancer (CRC) and hepatitis C virus (HCV) screening among patients aged 45-75years old receiving primary care at a federally qualified health center (FQHC) who are not currently up-to-date with both screenings and to examine implementation outcomes. Ten health center sites in the FQHC will be randomized in two waves using a stepped wedge design. Intervention strategies target the system, clinician, and patient levels. System-level strategies include a customized electronic health record best practice alert that pairs CRC and HCV screening and standard operating procedures. Clinician-level strategies include a training session and feedback on screening rates. Patient-level strategies include a theory-informed educational booklet about CRC and HCV screening in English or Spanish and access to stool DNA testing and HCV screening among 350 participants. The primary outcome is both CRC and HCV screening uptake at 12months post-intervention among 350 participants. System-wide CRC and HCV screening rates among patients 45-75years old also will be monitored. Implementation barriers and facilitators will be examined. The project is ongoing; effectiveness and implementation outcomes will be determined following study completion. Results may inform potential subsequent scale-up and offer insights for promoting multiple screening behaviors in a single intervention. NCT06745895 (date registered: 2024-12-20); https://clinicaltrials.gov/study/NCT06745895?cond=CRC%20AND%20HCV&rank=.

Repurposing dronedarone for colorectal cancer therapeutic via suppression of the AKT/ERK signaling pathways.

INHBB promotes liver metastasis of colorectal cancer via regulation of TGF-β/Smad signaling, EMT and anoikis resistance.

Insulin resistance is an important risk factor for the development of colorectal cancer (CRC), and triglyceride-glucose (TyG) related indices, as emerging biomarkers of insulin resistance, have not been thoroughly studied in the context of CRC risk assessment. This study aimed to evaluate the relationships between three TyG-related indices-specifically triglyceride glucose-body mass index (TyG-BMI), triglyceride glucose-waist circumference index (TyG-WC), and triglyceride glucose-waist to height ratio index (TyG-WHtR)-and CRC risk within a large prospective cohort from the Kailuan Study (2006-2019), which included 173,342 cancer-free participants. During a median follow-up of 14.23 years, 977 incident CRC cases were identified. Multivariable Cox proportional hazards models revealed significant positive associations between the TyG-related indices and CRC risk: for TyG-BMI, those in the third and fourth quartiles had hazard ratios (HRs) of 1.22 (95% CI: 1.01-1.48) and 1.35 (95% CI: 1.11-1.64), respectively; for TyG-WC, the fourth quartile had an HR of 1.43 (95% CI: 1.17-1.74); and for TyG-WHtR, the third and fourth quartiles had HRs of 1.28 (95% CI: 1.05-1.57) and 1.37 (95% CI: 1.12-1.68), respectively. Dose-response analyses demonstrated linear relationships for all indices (all p for overall = 0.001, p for non-linear >0.05). The results show a significant association between elevated TyG indices and increased colorectal cancer (CRC) risk, suggesting that these markers may have potential value in risk stratification.

Cancer-associated fibroblasts-derived exosomes in colorectal cancer progression: Mechanism and therapeutic opportunities.

Long-term prognostic value of cytokeratin 20 mRNA-positive cells in blood and bone marrow of patients with localized colorectal cancer.

Discovery of indolinone-based covalent ULK1 inhibitors that suppressed autophagy and induced apoptosis against colorectal carcinoma.

The critical role of epithelial-mesenchymal transition (EMT) in colorectal cancer progression and therapeutic outcomes.

DNA methylation-mediated extracellular matrix gene silencing in colorectal cancer.

Awareness of colorectal cancer and screening uptake in Eastern KSA: Predictors and implications.