Molecular Carcinogenesis最新文献

Triple-negative breast cancer (TNBC) is a particularly aggressive malignant tumor. Pachymic acid (PA), a bioactive triterpenoid, has demonstrated multi-target therapeutic effects in TNBC. However, the detailed molecular networks responsible for its anti-TNBC effects have not yet been fully elucidated. The therapeutic potential of PA was evaluated by measuring cell viability, proliferation, invasion, and migration. The impact on ferroptosis was assessed by detecting ROS, MDA, GSH, and Fe2⁺ levels. Animal xenograft experiments were used to analyze the role in vivo. Expression analysis was performed using immunoblot, quantitative PCR, and immunohistochemical assays. PA exhibited antiproliferative, anti-migratory, and anti-invasive effects on BT-549 and MDA-MB-231 cells in vitro. PA induced oxidative stress and triggered ferroptosis in BT-549 and MDA-MB-231 cells. Kinesin family member 18B (KIF18B) was overexpressed in TNBC and was reduced by PA treatment. KIF18B restoration counteracted PA-mediated antiproliferative, anti-migratory, anti-invasive, and pro-ferroptosis effects on BT-549 and MDA-MB-231 cells. Furthermore, restored expression of KIF18B attenuated the efficacy of PA in reducing xenograft growth in vivo. Our study demonstrates that PA suppresses TNBC progression by inducing ferroptosis and inhibiting malignant phenotypes through KIF18B downregulation, offering experimental evidence supporting the clinical potential of PA as a novel therapeutic agent for TNBC treatment.

Despite endometrial cancer (EC) being a malignancy linked to metabolic disorders such as diabetes and obesity, its prognostic markers and metabolic dysregulation remain incompletely understood. Gene expression profiles and clinical data were obtained from TCGA. Metabolism-regulating genes (MRGs) were identified by intersecting genes linked to diabetes, obesity, and EC prognosis. A prognostic MRG-model was developed using LASSO Cox regression. Functional pathway features of the MRG-model were analyzed for prognostic signals, immune status, and antitumor therapy using methods such as gene set enrichment analysis, GSVA, ssGSEA, EPIC, CIBERSORT, and others. Machine learning algorithms identified the optimal MRG, TCF21, for in vivo and in vitro validation through experiments including colony formation, CCK8 assays, wound healing, Transwell assays, measurement of reactive oxygen species and ATP levels. We identified 72 candidate genes related to EC metabolism and progression. The MRG-model effectively distinguished high-risk from low-risk EC patients and demonstrated strong prognostic predictive capacity. Significant differences were observed between the two groups in clinical factors, functional pathways, immune characteristics, mutation profiles, and treatment recommendations. TCF21, with optimal performance, was selected for further study. TCF21 expression was significantly downregulated in EC and correlated with DNA methylation. As a tumor suppressor, TCF21 regulates proliferation, migration, invasion, and mitochondrial metabolism in EC via PDE2A. The MRG-model can serve as a robust tool for prognostic prediction and support personalized EC treatment, enhancing its clinical potential. TCF21 is methylated in EC, and its regulation of PDE2A governs the malignant phenotype and mitochondrial metabolism.

Resistance to primary chemotherapeutics poses a significant challenge in treating solid tumors. The majority of the second-line chemo and targeted therapeutics act moderately/less effectively in drug-resistant tumors owing to the multicausal nature of drug resistance. Therefore, a single agent with pleiotropic effects would be beneficial in combating this adversity. Withania somnifera exhibits multifunctional anticancer properties, but its role in overcoming chemoresistance remains poorly understood. We evaluated the cytotoxic effect of Ashwamax^TM-W. somnifera (WS)-extract and Withaferin A (WFA), in intrinsically resistant (KATO-III and SKOV3) and acquired chemoresistant gastric (AGS^5FU) and ovarian (A2780^LR) cancer cellular models. We examined their impact on autophagy and apoptosis pathways and elucidated the underlying molecular mechanism. In vivo efficacy of WFA on cisplatin-paclitaxel-resistant epithelial ovarian cancer (EOC) xenografts was assessed using noninvasive optical imaging. Mechanistically, WFA is more proficient in targeting chemoresistant cells than Ashwamax^TM-WS extract and activates apoptosis by overriding the AKT-NF-κB-STAT3-survivin axis. Preclinical imaging revealed dose-dependent tumor regression (during and after treatment) in platinum-taxol-resistant EOC xenografts that were unresponsive to cisplatin challenge. WFA, at 3 mg kg^-1 dosage, reduced tumor volume by 4.7-fold compared to controls, with sustained antitumor effects persisting after treatment cessation. WFA effectively targets the AKT-NF-κB-STAT3-survivin axis to overcome single and multidrug resistance in gastric and epithelial ovarian cancers, presenting a promising therapeutic alternative for chemoresistant malignancies.

Cellular responses after oxidative stress-induced deoxyribonucleic acid (DNA) damage (e.g., DNA double-strand break) control tumor cell proliferation, senescence, and apoptosis. The nuclear ubiquitous casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) ensures replication feasibility by modulating double-strand break repair necessary to regulate tumor cell proliferation. However, the regulatory mechanism of NUCKS1 in oxidative stress-induced melanoma cell apoptosis is not well characterized. In this study, we reported reduced phosphorylation of NUCKS1 during oxidative stress-mediated melanoma A375 and A875 cell apoptosis, and silencing of NUCKS1 obviously promoted A375 and A875 cell apoptosis. Mechanistically, cyclin-dependent kinase 13 (CDK13) was identified as a major upstream kinase to phosphorylate NUCKS1 and downregulated via ataxia telangiectasia mutated (ATM)/checkpoint kinase 2 (Chk2)/cell division cycle 25C (Cdc25C) axis during the process of oxidative stress-induced apoptosis. Moreover, we found that p-NUCKS1 could bind to tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein Zeta (YWHAZ) and subsequently regulate the level of BCL2-associated X (Bax), thereby leading to melanoma A375 and A875 cell apoptosis. Furthermore, we found that p-NUCKS1 was highly expressed in tumor specimens from melanoma patients, and silencing of NUCKS1 inhibited tumor growth in melanoma A375 and A875-bearing mouse models. Therefore, p-NUCKS1 could act as a potential target for melanoma treatment by mediating oxidative stress-induced apoptosis.

Retraction: B. Sun, M. Chen, C. Hawks, P. J. Hornsby, and X. Wang, "Tumorigenic Study on Hepatocytes Coexpressing SV40 With Ras," Molecular Carcinogenesis 45 no. 4 (2006): 213-219, https://doi.org/10.1002/mc.20137. The above article, published online on 19 September 2005 in Wiley Online Library (wileyonlinelibrary.com) has been retracted by agreement between the authors; the journal Editor-in-Chief; and Wiley Periodicals LLC. The authors identified a significant discrepancy between the legend of Figure 3 and its corresponding description in the Results section. Specifically, the figure legend cites the use of "HCA2 cells," whereas the Results section explicitly describes experiments conducted with "human hepatocyte lines HL-7702 and HL-7703." To resolve this discrepancy and validate the critical findings, the authors attempted to replicate the experiments using the original HL-7702/HL-7703 cell systems. However, two irremediable constraints precluded verification: First, the extended time interval of nearly two decades since publication had rendered the original biological materials nonviable due to natural degradation. Second, essential plasmid constructs required for experimental replication were permanently lost during multiple laboratory relocations over this period. Consequently, the core conclusions remain experimentally unverifiable. Given that the figure-result contradiction cannot be resolved through standard correction measures and considering the irretrievable inability to replicate the study's key outcomes, we conclude that the continued availability of this paper irreparably compromises the validity of the study's conclusions and risks perpetuating misleading information. Therefore, the article must be retracted.

Emerging evidence suggests that Helicobacter pylori (H. pylori) infection may contribute to extra-gastric malignancies, but the mechanisms are unclear. Using untargeted metabolomics data from two prospective Chinese cohorts, we constructed an H. pylori associated metabolomic signature in 1800 baseline participants and evaluated cancer risks using conditional logistic regression in 1:1 matched case-control studies for lung cancer (n = 352 pairs), colorectal cancer (CRC; n = 190 pairs), esophageal cancer (n = 146 pairs), and hepatocellular carcinoma (n = 163 pairs), with confounder adjustment and sex stratification. Mediation analysis was performed to evaluate the mediating effects of the metabolomic signature and specific plasma metabolites on the observed associations. Mendelian randomization (MR) analysis was conducted to evaluate causal relationships. H. pylori infection was significantly associated with an increased risk of CRC (OR = 1.80, 95% CI: 1.13-2.85), especially driven by males (OR = 3.01, 95% CI: 1.44-6.31), but not with other cancers. Additionally, the H. pylori infection-related metabolomic signature consisting of 26 metabolites (OR per standard deviation [SD] increment = 1.52, 95% CI: 1.03-2.25) and plasma metabolite methionine sulfone (OR per SD increment = 1.73, 95% CI: 1.16-2.58) were positively associated with CRC risk in males. Mediation analysis indicated partial mediation by the metabolomic signature (12.08%, 95% CI: 0.26-46.88%) and methionine sulfone (16.79%, 95% CI: 0.11-74.76%). MR analysis further supported a potentially causal association between methionine sulfone and CRC (OR = 1.08, 95% CI: 1.02-1.15). Collectively, these results implicate sex-specific metabolomic alterations, particularly involving methionine sulfone, in mediating the relationship between H. pylori infection and CRC risk in males. These insights advance understanding of CRC pathogenesis and may inform targeted prevention strategies.

Gastric cancer (GC) is one of the most common cancers worldwide. Cancer cell metastasis is a major factor leading to poor prognosis. Previous proteomic data suggested that SSR4 might be closely associated with the occurrence and development of GC. However, the role and molecular mechanism of SSR4 in GC is not yet clear. The present study found that the expression level of SSR4 was increased in GC tissue and serum from GC patients. In addition, SSR4 could promote the malignant biological behavior of GC cells in vitro and in vivo. The mechanism may be that SSR4 regulates the expression of NDUFB11 and ATP6AP1, and then enhanced the function of mitochondrial respiratory chain complex I (CI) and mitochondrial respiratory chain complex V (CV), which promoted the mitochondrial oxidative phosphorylation and thus promoted GC progression. These findings expand the understanding of the role of SSR4 and provide a new target for the treatment of GC.

MYC is among the most frequently dysregulated oncogenes in human cancer, yet its direct targeting remains a significant challenge. Here, we present an in-silico integrative screening approach to identify compounds and combinations that can block MYC's oncogenic function by specifically disrupting its transcriptional regulatory function. Using a doxycycline (DOX)-inducible model, we established a MYC loss-of-function (LOF) gene signature that specifically captures the molecular consequences corresponding to the loss of MYC's ability in transcriptional regulation. By integrating large-scale post-perturbation transcriptomic profiling from the CMAP database, we screened over 8300 drug-induced profiles and identified 70 recurrent compounds that are predicted to antagonize MYC's transcriptional programs. To further enhance their therapeutic potential, we also developed an orthogonality analysis to pinpoint synergistic drug combinations that suppress MYC activity more effectively than single agents. Our scalable framework enables a rational and systematic identification of compounds with potential to antagonize MYC's oncogenic function by disrupting its transcriptional regulatory ability without necessarily decreasing its abundance. Our approach provides new insights on utilizing existing anticancer drugs to indirectly target MYC in MYC-driven cancer.

Melanoma, a highly malignant tumor originating from melanocytes, has seen a significant increase in global incidence, particularly among the elderly. Anti-PD-1 monoclonal antibodies, which activate the immune system to attack cancer cells by blocking the PD-1/PD-L1 signaling pathway, have improved survival rates but face challenges such as innate resistance. This study enrolls 37 melanoma patients and 7 benign nevus patients, with tissue samples collected for analysis. RT-qPCR and Western blot are used to quantify the expression of the target protein. Flow cytometry is utilized to analyze immune subsets in tumors. Glucose uptake, lactate production, and ATP level are assessed by commercial kits. Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) are measured using a Seahorse XF Analyzer. RNA Bisulfite Sequencing is performed to quantify pyruvate kinase M2 (PKM2) m7G methylation level, MeRIP-qPCR is conducted to validate the m7G methylation level of PKM2, and RIP assay is conducted to confirm POU4F1-METTL1 interaction. The results show that POU Class 4 Homeobox 1 (POU4F1) is upregulated in melanoma tissues compared to benign nevi. Anti-PD-1 treatment effectively reduces POU4F1 expression in sensitive B16-F10-M tumors and has no significant effect on resistant B16-F10-R tumors. POU4F1 overexpression induces profound metabolic alterations, including increased lactate production, glucose uptake, and ECAR, while suppressing OCR in B16-F10-M cells. POU4F1 overexpression also reduces the infiltration of CD8⁺ T cells, M1-macrophages, and NK cells, while increasing Treg and M2-macrophage populations in B16-F10-M cells. Importantly, 3-Bromopyruvate (a glycolysis inhibitor) reverses these effects. Mechanistically, POU4F1 upregulates METTL1 expression and increases m7G methylation of PKM2 mRNA. Besides, there is an interaction between POU4F1 and METTL1. METTL1 is also overexpressed in melanoma tissues compared to benign nevi. In conclusion, POU4F1 drives anti-PD-1 resistance in melanoma by enhancing glycolysis via METTL1-mediated m7G methylation of PKM2. Targeting the POU4F1-METTL1-PKM2 axis may improve melanoma immunotherapy outcomes.

This study investigates the correlation between CRC and lysosomal-dependent cell death (LDCD) to identify potential therapeutic targets and prognostic indicators. Utilizing CRC datasets (TCGA-CRC) and GSE17538, differentially expressed genes and LDCD-related genes (LDCDRGs) were analyzed to identify candidate genes. A risk model was constructed using Cox regression analysis, proportional hazards test and least absolute shrinkage and selection operator analysis. Independent prognostic factors were determined through Cox analysis (univariate and multivariate). Additionally, nomogram establishment, enrichment analysis, tumor immune microenvironment analysis, sensitivity analysis of chemotherapeutic drugs and single-cell sequencing analysis were conducted. Furthermore, prognostic gene expression in CRC and normal groups was further evaluated in TCGA-CRC as well as in clinical samples. A total of 37 candidate genes were identified. ATP6V0A4, CLU and IL13RA2 were selected for constructing a risk model. The risk model, incorporating independent prognostic parameters such as risk score, age and pathological T stage, exhibited favorable diagnostic performance for CRC. Tumor immune microenvironment analysis showed higher dysfunction, exclusion, and tumor immune dysfunction and exclusion scores in the high-risk group compared to the low-risk group. Significant differences were observed in the 50% inhibitory concentration of 84 drugs between the two risk subgroups. ENCs and myeloid cells were regarded as key cells. Importantly, IL13RA2 exhibited higher expression in patients with CRC, while CLU was more highly expressed in normal samples. This study identified ATP6V0A4, CLU and IL13RA2 as potential biomarkers associated with lysosome-mediated cell death in CRC, providing insights for diagnosis and treatment.