Molecular Carcinogenesis最新文献

This study explored the effect of ubiquitin-specific protease 4 (USP4) on mitochondrial dynamics in esophageal squamous cell carcinoma (ESCC). USP4 and phosphoglycerate mutase 5 (PGAM5) expression in ESCC tissues was measured. ESCC cells were subjected to gain- and loss-of-function experiments, followed by examinations of proliferation, invasion, migration, apoptosis, light chain 3 (LC3), P62, Bcl2-associated X (Bax), B-cell lymphoma 2 (Bcl2), Cytochrome c (CytC), caspase3, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS), and ROS. An in vivo tumor formation model of ESCC was established for in vivo verification. The relationship between USP4 and PGAM5 was analyzed. USP4 and PGAM5 expression was high in ESCC tissues. Mechanistically, USP4 eliminated K48-linked ubiquitin chains to maintain PGAM5 stability. PGAM5 knockdown impaired malignant behaviors of ESCC cells, reduced LC-3I-to-LC-3II conversion, increased mtROS, ROS, and P62 levels, activated the caspase-dependent mitochondrial pathway, and decreased MMP. Overexpressing USP4 increased MMP and Bcl2 expression while lowering Bax, CytoC, cleaved caspase3, and mtROS levels in ESCC cells, which was nullified by PGAM5 knockdown. Ectopic USP4 accelerated tumor growth in mice, which was reversed by PGAM5 knockdown. Collectively, USP4 promotes cell growth and excessive mitophagy in ESCC by stabilizing PGAM5.

Alternative splicing of FOXM1 produces different isoforms, which have been proven to exist and have complex functions. One of the isoforms of FOXM1, isoform ENST00000535350, is a short noncoding RNA sequence, designated as FOXM1s here. We determined the function and mechanism of FOXM1s-encoded peptide, FOXM1s, in the development and progression of pancreatic cancer. The expression of FOXM1s as noncoding RNA in pancreatic cancer tissues and cell lines was analyzed by RT-PCR. Gene expression and its association with clinicopathologic characteristics of patients with PDAC were analyzed using IF and bioinformatics. The effects on cell proliferation, migration, invasion, tumor stemness, and on PI3K/AKT signaling were evaluated through in vitro biology methods and functionally validated in mouse models by using overexpression and knockdown approaches. The expression of FOXM1s in human pancreatic cancer tissues and cell lines was significantly increased. The overexpression of FOXM1s had a promoting effect on pancreatic cancer, while the mutation of FOXM1s attenuated its effect, indicating that FOXM1s exerted its role potentially through ORF2-encoded a peptide. The specific antibody #FOXM1s was used to validate that FOXM1s expressed a predicted peptide, FOXM1s, and its expression was upregulated in pancreatic cancer. FOXM1s significantly promoted the proliferation, migration, and invasion of pancreatic cancer cells, facilitated liver metastasis, and upregulated the expression of stem-related genes in pancreatic cancer. Mechanistically, the FOXM1s peptide encoded by FOXM1s activated the PI3K/AKT signaling pathway. FOXM1s encodes a FOXM1s peptide and exhibits oncogenic function in the pancreatic cancer development progression at least in part through activating PI3K/AKT signaling pathway. This novel molecule could serve as a potential therapeutic target.

The solute carrier protein SLC5A6 is associated with multiple malignant tumors, while its role in cervical cancer (CC) remains unexplored. This study aimed to investigate the expression pattern, biological functions, and underlying mechanisms of SLC5A6 in cervical cancer. It was found that the expression of SLC5A6 was significantly upregulated in cervical cancer tissues, and its high expression was associated with poorer overall survival of patients. In vitro functional experiments conducted in HeLa and SiHa cell lines demonstrated that overexpression of SLC5A6 enhanced cell proliferation, colony formation, and migration abilities, while inhibiting cell apoptosis; conversely, knockdown of SLC5A6 suppressed these oncogenic phenotypes. Further in vivo experiments confirmed that knockdown of SLC5A6 could inhibit the growth of xenograft tumors. Through transcriptomic analysis and pathway enrichment analysis, this study identified lipid metabolism as a key downstream pathway of SLC5A6, in which fatty acid synthase (FASN) serves as a crucial effector molecule. Mechanistically, SLC5A6 is responsible for the transmembrane transport of biotin. Reduced expression of SLC5A6 leads to a decrease in the expression of biotin-dependent acetyl-CoA carboxylase (ACC), which in turn downregulates its downstream target gene FASN. Importantly, knockdown of FASN could reverse the promotional effect of SLC5A6 overexpression on the growth of cervical cancer cells, indicating that SLC5A6 promotes cervical cancer progression through FASN-mediated reprogramming of lipid metabolism. In conclusion, this study identified SLC5A6 as a novel oncogenic factor in cervical cancer and reveals its mechanism of regulating lipid metabolism via FASN, suggesting that targeting the SLC5A6-FASN axis may serve as a potential therapeutic strategy for cervical cancer.

The m⁵C RNA modifications have been implicated in the pathogenesis of urothelial carcinoma and hold potential as prognostic biomarkers for muscle-invasive bladder cancer (MIBC) patients. In this study, we developed an MIBC-risk model by integrating m⁵C modification-related genes and differentially expressed genes using Nanopore sequencing and a machine learning approach. Compared to our previous research, we observed that m⁵C modifications are more functional, with the most enriched regions being the 3'UTR and exons. Our analysis revealed differential m⁵C methylation sites in several well-characterized cancer-related genes, including BMI1, PTEN, MALAT1, FADD, STAT5A, BIRC6, FOXO3, CCNG1, PAK2, UBE2L3, SMARCB1, and TUG1. Functional enrichment analysis demonstrated significant involvement of these genes in key oncogenic pathways, particularly DNA damage response, double-strand break repair, p53 signaling, MAPK cascade, NF-κB signaling, and cell proliferation/migration pathways. Unlike models based on single factors, the combination of m⁵C modification-related genes and differentially expressed genes resulted in a more effective classification model. This approach yielded an optimized 11-gene prognostic signature comprising GGA1, NUMBL, ECHDC2, NLRC5, EIF2D, GJA1, XPC, DAZAP2, C6orf120, WDR45, and CES1, which demonstrated superior predictive performance in TCGA MIBC patients. These findings establish m⁵C RNA modification patterns as promising molecular signatures for MIBC prognosis and potential therapeutic targets.

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.