Molecular Carcinogenesis最新文献

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.

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.

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.

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.

Papillary thyroid cancer (PTC) often presents as anatomically distinct foci in bilateral lobes. However, it remains controversial whether these foci arise independently from distinct malignant progenitor cells or result from the dissemination of the primary lesion. Fifteen pairs of bilateral PTC at Stage I were enrolled, and sequencing was performed using a 437-cancer-gene panel (Geneseeq). The entire mitochondrial DNA (mtDNA) was also sequenced and analyzed. The genetic alterations and molecular profiles were comprehensively analyzed and compared between the paired bilateral tumors. Fourty-eight mutations were detected in the nuclear genome, all of which were somatic and heteroplasmic. Among these, BRAF^V600E mutation was predominant (25/30, 83.3%). In mtDNA, three mutations (10963A-C, 13193T-C, 13341 C-G) were identified as novel, seven heteroplasmic mutations were detected including six somatic mutations. Discordant genetic alterations were observed between the paired tumors in 86.7% (13/15) of bilateral PTC cases. Our results reveal that the majority of early-stage bilateral PTCs develop from independent malignant clones harboring different genetic backgrounds, which provides insights into the pathogenesis of bilateral PTCs and supports individualized clinical decision-making.

Tobacco smoke is a major risk factor for esophageal squamous cell carcinoma (ESCC), yet only a subset of smokers develop this disease, implicating gene-smoking interactions in modulating individual susceptibility. Through integrative transcriptomic analyses of normal and tumor samples from smokers and nonsmokers, we identify four smoke-responsive genes (CXCL14, HORMAD1, WFDC5, and MPZ) as potential contributors to ESCC carcinogenesis. Among these, HORMAD1 is markedly upregulated in ESCC cells upon exposure to cigarette smoke condensate (10 µg/mL), benzo[a]pyrene (3 µM), or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (10 µM), correlating with activation of error-prone nonhomologous end joining (NHEJ) in response to DNA damage. Notably, smokers with higher HORMAD1 expression levels exhibit enhanced NHEJ but impaired homologous recombination (HR), leading to increased genomic instability. Through a two-stage case-control study involving 5151 ESCC cases and 5963 controls, we identify two regulatory variants of HORMAD1, rs11204679 and rs33924488, significantly associated with ESCC risk through a gene-smoking interaction (p_interaction = 0.0027). Both variants confer a protective effect among smokers (OR = 0.80, 95% CI: 0.74-0.87, p = 9.58 × 10^{- 8}) but not in nonsmokers (OR = 0.98, 95% CI: 0.90-1.06, p = 0.5950). Mechanistically, the rs11204679 G > C and rs33924488 GA > G- variants attenuate HOXA6 and SOX15 binding at a distal enhancer, respectively, suppressing HORMAD1 expression via long-range chromatin interactions. These findings establish HORMAD1 as a critical mediator of tobacco-related DNA repair dysregulation and a potential biomarker for ESCC risk stratification and precision prevention.

Ultraviolet A (UVA) radiation induces DNA damage both directly, by forming cyclobutane pyrimidine dimers (CPDs), and indirectly, by generating oxidative stress. Cells rely on nucleotide excision repair (NER) and translesion synthesis (TLS) to tolerate these lesions. Xeroderma pigmentosum variant (XP-V) cells, deficient in DNA polymerase eta (pol eta), exhibit a heightened risk of skin cancer due to impaired TLS. While XP-V patients are considered NER-proficient, our findings challenge this assumption by demonstrating that UVA-induced oxidative stress impaired NER activity, leading to increased C > T transitions at CPD sites. Whole-exome sequencing of UVA-irradiated XP-V cells revealed a substantial rise in mutations, with a distinct C > T signature characteristic of defective CPD repair. Notably, pretreatment with the antioxidant N-acetylcysteine (NAC) mitigated this effect, reducing C > T transitions through enhanced NER function and decreasing C > A transversions via its antioxidant properties. These results redefine the mutagenic landscape of XP-V cells, revealing that oxidatively generated damage to NER proteins-rather than TLS deficiency alone-contributes to their elevated mutation burden. Our findings suggest that antioxidant strategies may partially protect XP-V patients from UVA-driven mutagenesis enhancing the cells' DNA repair capacity, ultimately reducing skin cancer and contributing to better overall health outcomes.

Carfilzomib, a second-generation proteasome inhibitor approved for the treatment of multiple myeloma, is a highly potent and selective inhibitor of the CT-L activity of the i20S proteasome. Several studies have shown that carfilzomib (CFZ) can bypass resistance to bortezomib; however, its impact on squamous cell carcinoma of the head and neck is not well understood. This study aimed to evaluate the anticancer potential of CFZ in head and neck cancer cells (HNSCC) by examining its effects on proliferation, apoptosis, and the underlying mechanisms in both HPV-positive and HPV-negative HNSCC. In Vitro validation of CFZ showed an IC50 that was more than fourfold lower in HPV-negative CAL-27 than other HNSCC cell lines. In addition, CFZ inhibited p-Akt and p-S6 and activated p21, which increased growth inhibition and apoptosis in CAL-27 cells. In mice bearing xenografted HPV-negative CAL-27 cells, we confirmed that CFZ reduced tumor growth. Collectively, the cytotoxic effects induced by CFZ involve cell growth inhibition and apoptosis via the PI3K/AKT/mTOR and p21 signaling pathways. This suggests that CFZ is a novel therapeutic agent that can overcome the existing cisplatin resistance used in the treatment of HPV-negative HNSCC.

Gastric cancer (GC) is a highly prevalent and lethal malignancy. This study aims to investigate the role of Growth Differentiation Factor 15 (GDF15) in regulating ferroptosis through the p62/Keap1/Nrf2 pathway and to elucidate its impact on GC progression. GDF15 levels were assessed via Western blot (WB) analysis in both human gastric mucosal cells and GC cell lines. Cellular viability and growth were evaluated using CCK-8 assays and colony formation experiments. Cell migration and invasion capabilities were assessed using wound healing and Transwell assays. Levels of ROS, MDA, GSH, GPX4, and Fe²⁺ in cells were measured using assay kits. JC-1 method was utilized for evaluating mitochondrial membrane potential. Tumor weight changes were recorded in BALB/c nude mouse models. GDF15 was highly expressed in GC cells, and sh-GDF15 inhibited the growth and metastasis of GC cells, increased the expression of ROS and MDA in cells, promoted cell ferroptosis, and inhibited the p62/Keap1/Nrf2 pathway in cells (p < 0.05). Compared to the sh-GDF15 group, treatment with the Nrf2 activator, NK-252 reduced ROS and MDA levels, suppressed ferroptosis, and enhanced the activation of the p62/Keap1/Nrf2 signaling pathway in GC cells. In GC tissues, the sh-GDF15 group showed reduced tumor volume and weight, elevated Keap1, ROS, and MDA expression, decreased p62 and Nrf2 levels, and increased ferroptosis, which were reversed by the addition of NK-252 (p < 0.05). Conclusively, silencing GDF15 inhibits the p62/Keap1/Nrf2 pathway, promoting ferroptosis and suppressing GC progression.

Retraction: M. Tan, D. Zhang, E. Zhang, D. Xu, Z. Liu, J. Qiu, Y. Fan, and B. Shen, "SENP2 Suppresses Epithelial-Mesenchymal Transition of Bladder Cancer Cells Through deSUMOylation of TGF-βRI," Molecular Carcinogenesis 56, no. 10 (2017): 2332-2341. https://doi.org/10.1002/mc.22687. The above article, published online on 02 June 2017, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by Wiley Periodicals LLC. A third party reported to the journal that image elements in Figure 2E of this article had been duplicated and manipulated from a previously published article by a different group of authors and reporting different experimental conditions (Mani et al. 2007 [https://doi.org/10.1073/pnas.0703900104]). Further investigation by the publisher confirmed this duplication and also detected additional duplications between the T24-Vector panel of Figure 5A and the first panel of Figure 5B, as well as duplication and rotation of image elements in the T24-SENP2 panel of Figure 5A and the third panel of Figure 5B. The authors responded to an inquiry by the publisher and stated that there were no issues of duplication between different articles and that the duplications in Figure 5 may have been caused by errors during image preparation. However, the authors were unable to provide original, unmodified data or images for the experiments reported. The retraction has been agreed to because of the duplication of images from another article, as well as duplication and rotation of images and image elements within the same article, which fundamentally compromises the reported conclusions. The authors have stated their consent to the retraction. The authors disagree with the retraction as they have stated they do not agree that image elements were duplicated in Figure 2E.