MDM4 is one of the major regulators of p53. The biological effect of MDM4 on tumor is controversial, its role and molecular mechanism in colon cancer progression and prognosis are still unclear. In this study, we identify that MDM4 is significantly overexpressed in human colon cancer and high MDM4 expression was associated with poor prognosis of colon cancer with mutant p53. MDM4 inhibits the ubiquitination of the ferroptosis marker protein GPX4 at K167 and K191 by upregulating the protein expression level of the E3 ubiquitin ligase TRIM21, which promotes the polyubiquitination of GPX4 transfer from K48- to K63- linked ubiquitination. Thereby, MDM4 enhances the stability of GPX4 protein, inhibiting ferroptosis, increasing the resistance of colon cancer patients to chemotherapy, and promoting colon cancer progression. These findings elucidate the ferroptosis inhibition effect of MDM4 via regulating TRIM21/GPX4 on p53-mutated colon cancer and provide a potential therapeutic strategy for colon cancer therapy.

MDM4 is one of the MDM protein family and is generally recognized as the key negative regulator of p53. As a cancer-promoting factor, it plays a non-negligible role in tumorigenesis and development. In this article, we analyzed the expression levels of MDM4 in pan-cancer through multiple databases. We also investigated the correlations between MDM4 expression and prognostic value, immune features, genetic mutation, and tumor-related pathways. We found that MDM4 overexpression is often accompanied by adverse clinical features, poor prognosis, oncogenic mutations, tumor-immune infiltration and aberrant activation of oncogenic signaling pathways. We also conducted transcriptomic sequencing to investigate the effect of MDM4 on transcript levels in colon cancer and performed qPCR to verify this. Finally, we carried out some in vitro experiments including colony formation assay, chemoresistance and senescence-associated β-galactosidase activity assay to study the anti-tumor treatment effect of small molecule MDM4 inhibitor, NSC146109. Our research confirmed that MDM4 is a prognostic biomarker and potential therapeutic target for a variety of malignancies.

Colorectal lateral spreading tumours (LST), early-stage lesions of colorectal cancer (CRC), are associated with gut microbiota dysbiosis. However, the functional alterations in gut microbiota and their metabolic pathways remain inadequately understood. This study employed propensity score matching to compare 35 LST patients with 35 healthy controls. Metagenomic and metabolomic analyses revealed notable differences in gut microbiota composition and metabolic pathways. LST patients exhibited a marked reduction in short-chain fatty acid (SCFA)-producing probiotics, such as Roseburia, Clostridium, and Butyricicoccus sp-OF13-6, alongside anti-inflammatory metabolites. In contrast, potential intestinal pathogens linked to inflammatory bowel disease (IBD), including Escherichia and Citrobacter amalonaticus, were significantly enriched. Orthogonal partial least squares discriminant analysis (OPLS-DA) highlighted significant metabolic disparities between the groups, with enrichment in pathways associated with cholesterol metabolism, choline metabolism in cancer, and amino acid metabolism - all relevant to cancer progression. Key biomarkers identified for LST included fumarate, succinate, glutamic acid, glycine, and L-aspartic acid, which were closely linked to these pathways. Functional studies demonstrated that these metabolites promoted the proliferation and invasion of HCT-116 and SW480 human colorectal cancer cells in vitro. Metagenomic and metabolomic analysis revealed a strong positive correlation between Escherichia and Ruminococcus sp-AM41-2AC abundance and the enriched pathways, whereas reductions in Roseburia species, including Roseburia-OF03-24 and Roseburia intestinalis_CAG13-exhibited negative correlations. These results suggest that gut microbiota and metabolite alterations in LST contribute to intestinal inflammation and CRC development, underscoring their potential as biomarkers for early detection and therapeutic targets.

Background and aims: Endoscopic submucosal dissection (ESD) is a pivotal technique for excision of early-stage esophageal tumors. However, its primary complication, postoperative esophageal stricture, is a significant challenge owing to the absence of effective preventive measures. Adipose-derived stem cells (ADSCs) have emerged as a promising treatment modality to address this concern. In this study, we aimed to investigate, for the first time, the efficacy of allogenic ADSC injections in preventing esophageal stenosis after ESD. Methods: We administered allogeneic ADSC injections (same-species but different individual) to a porcine model of ESD as a way to observe the role of ADSC in preventing esophageal stricture. We also co-cultured rats’ ADSCs with rats’ esophageal fibroblasts and esophageal mucosal epithelial cells to investigate the mechanism. Results: ADSCs notably facilitated epithelial–mesenchymal transition of epithelial cells. Furthermore, ADSC-conditioned medium exhibited a substantial inhibitory effect on fibroblast proliferation and migration, which was mediated by the transforming growth factor-beta pathway. Conclusions: Our findings underscore the potential of ADSC injections as a promising therapeutic intervention to enhance recovery and prevent post-ESD complications.

Purpose: This study aimed to assess the safety and efficacy of endoscopic submucosal dissection (ESD) and pre-cutting endoscopic mucosal resection (pEMR) in treating non-ampullary duodenal subepithelial lesions (NADSELs) and to evaluate the clinical utility of endoscopic ultrasound (EUS) before endoscopic resection (ER). Methods: In this retrospective single-centre cohort study, we compared the clinical outcomes of patients with NADSELs who underwent ESD or pEMR between January 2014 and June 2023. The accuracies of EUS in determining the pathological type and origin of the lesions were evaluated using postoperative histopathology as the gold standard. Results: Overall, 56 patients with NADSELs underwent ER in this study, including 16 and 40 treated with pEMR and ESD, respectively. There were no significant differences between the two groups in terms of en bloc resection rate, complete (R0) resection rate, perioperative complication rate, and postoperative hospital length of stay (P > 0.05). However, the pEMR group had significantly shorter median operational (13.0 min vs. 30.5 min, P < 0.001) and mean fasting (1.9 days vs. 2.8 days, P = 0.006) time and lower median hospital costs (¥12,388 vs. ¥19,579, P = 0.002). The accuracies of EUS in determining the pathological type and origin of the lesions were 76.8% and 94.6%, respectively, compared with histopathological evaluation. Conclusions: EUS can accurately predict the origin of NADSELs. Suitable lesions determined to originate from the submucosa or more superficial layers using EUS can be treated using pEMR as it shortens the operational and recovery time, reduces hospitalisation costs, and achieves an R0 resection rate similar to ESD.

Objective: This study sought to evaluate the effectiveness of the w-eCura system in determining the necessity of salvage surgery after non-radical endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) and to compare its efficacy with the eCura system. Methods: This retrospective case-control study was conducted at Fujian Provincial Hospital and included 290 patients with EGC who underwent ESD between January 2011 and July 2024. All patients were confirmed with non-radical resection upon pathological evaluation. Various clinicopathological characteristics such as gender, age, lesion location, size, Paris classification, histological type, depth of invasion, ulceration, lymphatic and venous invasion, and margin status were documented. Subsequent salvage procedures, lymph node involvement, and recurrence were monitored. Risk stratification was performed using the w-eCura and eCura systems, and the Cox proportional hazards model was employed to identify factors influencing positive cancer residue status (CRS). Survival analysis was conducted using Kaplan-Meier curves, and the predictive performance of the two models was compared using receiver operating characteristic (ROC) curves. Results: The study included patients with a mean age of 64.42 ± 9.35 years and a median maximum tumor diameter of 4.50 cm, who were monitored for a median duration of 32 (range 15–54) months. Factors such as w-eCura grade, horizontal resection margin, depth of invasion, lymphatic invasion, and venous invasion exhibited significant associations with CRS-positive classification (P < .05). A higher w-eCura grade was linked to an elevated risk of CRS-positive classification. Utilizing Cox proportional hazard models, we identified that lesion location (The middle 1/3 stomach), w-eCura grade (high and intermediate), and infiltration depth (SM2 and SM3) independently influenced CRS-positive classification. Kaplan-Meier survival analysis demonstrated a significant correlation between both eCura and w-eCura grades and survival time (Logrank P < .001). Notably, the w-eCura classification displayed enhanced sensitivity in detecting high-risk patients promptly. ROC curve analysis revealed that the w-eCura model exhibited an area under the curve (AUC) of 0.82, surpassing the eCura model’s AUC of 0.79 and underscoring the superior predictive accuracy of the w-eCura model for CRS-positive classification. Within the intermediate-risk w-eCura subgroup, positive vertical resection margin and SM3 infiltration depth emerged as independent factors influencing CRS-positive classification. Conclusion: The w-eCura system demonstrated superiority as a tool for assessing the necessity of salvage surgery following non-curative ESD in EGC compared to the eCura system. For patients presenting intermediate-risk, the w-eCura system in conjunction with positive vertical resection margin or SM3 depth of invasion, additional salvage surgery is advised for consideration.