Carcinogenesis最新文献

{"title":"Characteristic genetic alterations associated with the partial deletion of chromosome 11 in mouse thymic lymphomas induced by high-linear energy transfer irradiation with carbon ions.","authors":"Masaaki Sunaoshi, Erika Takahashi, Yoshiko Amasaki, Takamitsu Morioka, Kazuhiro Daino, Mayumi Nishimura, Yoshiya Shimada, Daisuke Iizuka, Shizuko Kakinuma","doi":"10.1093/carcin/bgag025","DOIUrl":"10.1093/carcin/bgag025","url":null,"abstract":"<p><p>High-linear energy transfer (LET) radiation is thought to induce highly complex DNA damage compared with photon radiation such as X-rays, suggesting a characteristic mechanism for the development of cancers associated with high-LET radiation exposure. However, few studies have investigated the carcinogenic mechanisms that are dependent on radiation quality or LET. This study analyzed mutations and gene expression in thymic lymphomas (TL) induced by high-LET carbon-ion irradiation to identify characteristic genetic alterations. The results revealed that TL arising after four-fractionated high-LET carbon-ion irradiation frequently exhibited loss of heterozygosity (LOH) in the region containing the TL-associated gene Ikzf1 on chromosome 11 owing to extensive genomic deletions in the paternal allele. Nevertheless, for carbon ion-induced TL, those with only LOH without Ikzf1 alterations were observed at a relatively high frequency (16/39, 41.0%). Comprehensive RNA sequencing and reverse-transcription PCR analysis of neighboring genes of Ikzf1 revealed highly upregulated expression of Grb10 (17/39, 43.6%), an imprinted gene that is barely expressed in the normal thymus. In TL expressing Grb10, enhanced interferon signaling and Pten mutations, along with activation of the PI3K-AKT-mTOR signaling pathway, were suggested to promote cell proliferation and survival. These results suggest that extensive genomic deletions caused by high-LET carbon-ion irradiation may contribute to carcinogenesis by altering the expression of multiple genes located in the deleted region.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic stress promotes oral squamous cell carcinoma progression via GLUD1-mediated metabolic reprogramming.","authors":"Huiqing Long, Yu Zhang, Yuqi Qin, Fangzhi Lou, Yiyun Liu, Juncai Pu, Xiaogang Zhong, Li Yan, Shihong Luo, Ping Ji, Bing Yang, Xin Jin","doi":"10.1093/carcin/bgag022","DOIUrl":"10.1093/carcin/bgag022","url":null,"abstract":"<p><p>Stress is a risk factor for the development of various types of cancer. However, its impact and related underlying mechanisms in oral squamous cell carcinoma (OSCC) progression remain unclear. Therefore, the present study aimed to investigate how chronic stress affects OSCC progression. We assessed mitochondrial metabolism by investigating tumor growth and performing behavioral analysis and molecular assessment, including non-targeted metabolomics and U-13C5-glutamine isotope metabolic flow analysis. We knocked down glutamate dehydrogenase 1 (GLUD1) using lentiviral vectors and investigated it both in vitro (HSC3 and HN6 cells) and in vivo (xenograft models). Our results indicated that chronic stress enhanced glutamate oxidative deamination and tricarboxylic acid cycle metabolism in OSCC cells. It also increased α-ketoglutarate (α-KG) levels, adenosine triphosphate synthesis, and oxygen consumption. Notably, GLUD1-knockdown suppressed these metabolic pathways and significantly inhibited tumor growth both in vitro and in vivo. Furthermore, under chronic stress, GLUD1 regulated OSCC progression through histone H3 trimethylation at lysine 4. However, α-KG supplementation partially reversed GLUD1-knockdown-induced OSCC progression inhibition. Collectively, our results indicate that the glutamate-dependent metabolic phenotype regulated by the GLUD1-α-KG metabolic axis is involved in the progression of OSCC under chronic stress.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of black raspberry lozenges on 4-hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in buccal cells and urinary levels of N'-nitrosonornicotine and its glucuronide in active smokers.","authors":"Kun-Ming Chen, Nicolle M Krebs, Yuan-Wan Sun, Dongxiao Sun, Jiangang Liao, Lisa Reinhart, Susan R Mallery, Karam El-Bayoumy","doi":"10.1093/carcin/bgag019","DOIUrl":"10.1093/carcin/bgag019","url":null,"abstract":"<p><p>The tobacco constituent, N'-nitrosonornicotine (NNN) is a potential etiological agent in the development of oral cancer. NNN is metabolically activated to form DNA adducts that release 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) which was detected at higher levels in the oral cavity of smokers than non-smokers. Black raspberry (BRB) has been proposed as a preventive agent of oral cancer. In a phase 0 clinical trial, 40 active smokers (16 males, 24 females) consumed 5 g of BRB lozenges daily for 8 weeks. Each participant served as his/her own control. Buccal cells and urine were collected at baseline, during BRB administration, and washout period. In all smokers, BRB reduced, but not significantly, the levels of HPB-releasing DNA adducts (Baseline: 0.97 ± 0.51 and End-BRB: 0.61 ± 0.23 HPB/106 Guanine). A sex-specific response to BRB was observed: BRB had no effects in men, but in 16 of 24 women, BRB significantly reduced the levels of HPB. We further tested the hypothesis that detoxification of NNN via N-glucuronidation by BRB may, in part, account for the inhibition of HPB levels. The ratio of NNN-N-glucuronide to free NNN significantly increased (P = 0.028) from 1.29 ± 0.40 (baseline) to 2.77 ± 0.76 (End-BRB) in all 40 women as well as in female responders from 1.24 ± 0.60 (baseline) to 2.87 ± 1.00, but not in non-responders. The metabolic changes of NNN observed in our clinical trial indicate that BRB is a promising candidate for cancer interception and prevention of oral cancer in some, but not in all active smokers.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13174947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Arsenic disulfide synergizes with the phosphoinositide 3-kinase inhibitor PI-103 to eradicate acute myeloid leukemia stem cells by inducing differentiation.","authors":"","doi":"10.1093/carcin/bgag018","DOIUrl":"https://doi.org/10.1093/carcin/bgag018","url":null,"abstract":"","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":"47 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction: ARHGAP24 inhibits cell proliferation and cell cycle progression and induces apoptosis of lung cancer via a STAT6-WWP2-p27 axis.","authors":"","doi":"10.1093/carcin/bgag028","DOIUrl":"https://doi.org/10.1093/carcin/bgag028","url":null,"abstract":"","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":"47 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148041312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction: Mechanism of 4-HPR-induced apoptosis in glioma cells: evidences suggesting role of mitochondrial-mediated pathway and endoplasmic reticulum stress.","authors":"","doi":"10.1093/carcin/bgag024","DOIUrl":"https://doi.org/10.1093/carcin/bgag024","url":null,"abstract":"","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":"47 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148027366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultraviolet A plays a protective role in ultraviolet B-induced squamous cell carcinoma through c-Fos/XRCC4 axis.","authors":"Yifei Xie, Ke Yao, Yongfeng Wu, Caoyuan Ding, Sally E Dickinson, Jian Li, Yanan Jiang, Simin Zhao, Eunmiri Roh, Kangdong Liu, Zigang Dong","doi":"10.1093/carcin/bgag014","DOIUrl":"10.1093/carcin/bgag014","url":null,"abstract":"<p><p>For decades, there has been a strong epidemiological association between solar ultraviolet (UV) radiation and skin cancer. UVB and UVA are the major UV bands that can penetrate the atmosphere, playing vital roles in skin carcinogenesis. Our research group previously discovered that a specific dose of UVA can inhibit the increase of activator protein 1 (AP-1) activity caused by UVB. It is unclear whether UVA plays a particular role in UVB-induced skin cancer. Here, we report that UVA was protective in UVB-induced cutaneous squamous cell carcinoma (cSCC) by attenuating UVB-induced DNA damage. DNA repair chip array results showed that the mRNA level of X-ray cross-complementing protein 4 (XRCC4) significantly increased in the UVA/B group compared with the UVB group, and knockdown of XRCC4 partly blocked the protective effect of UVA in UVB-induced DNA damage. AP-1, the predicted transcriptional regulatory factor of XRCC4, exhibited no sensitivity to UVB radiation upon pretreatment with UVA. More importantly, the luciferase reporter assay showed that c-Fos, which is the critical component of AP-1, inhibited the transcription of XRCC4, and mutation of c-Fos (cys154 > serine) partly enhanced this effect and promoted keratinocyte transformation. UVA was protective in UVB-induced cSCC by interacting with the c-Fos/XRCC4 axis.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the physiological relevance of the bioactivation of tobacco-specific carcinogen NNK and its metabolite NNAL: quantitative analyses of hydrolysis products from their protein adducts under different carcinogen exposure conditions.","authors":"Breanne Freeman, Tengfei Bian, Gujie Xu, Meghann Wheeler, Naomi Fujioka, John Malaty, Frank A Orlando, Dejana Braithwaite, Ramzi G Salloum, Adriaan W Bruijnzeel, Weizhou Zhang, Chengguo Xing","doi":"10.1093/carcin/bgag031","DOIUrl":"10.1093/carcin/bgag031","url":null,"abstract":"<p><p>4-(Methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its major metabolite 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are tobacco-specific lung carcinogens. NNK is widely used in preclinical models to induce lung tumorigenesis for elucidating carcinogenesis mechanisms and developing preventive agents, because of the high tumour burden in a cost-effective manner. Typical NNK doses employed in these models substantially exceed levels in humans and the routes of administration (e.g. intraperitoneal injection, oral gavage, or delivery via drinking water) differ fundamentally from inhalational exposure through cigarette smoke. At the molecular level, NNK and NNAL undergo metabolic bioactivation by cytochrome P450 enzymes, generating reactive intermediates capable of covalently modifying DNA and proteins, thereby initiating carcinogenesis. NNK and NNAL are also subject to competing metabolism. Their portion undergoing carcinogenic bioactivation is expected to vary as a function of dose and route of exposure, raising concerns about the physiological relevance of these preclinical models. Systematic comparison of NNK and NNAL bioactivation profiles in humans with these preclinical models can help assess their physiological relevance and inform translational application. Using LC-MS/MS methods, this study quantified 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB, an NNK-derived bioactivation hydrolysis product) and 1-(3-pyridyl)-1,4-butanediol (PBD, an NNAL-specific bioactivation hydrolysis product) in lung, liver, and serum samples from two mouse models and in human lung and plasma samples. Marketed differences were observed between NNK intraperitoneal preclinical models and human samples; in contrast, the tobacco smoke-based preclinical model better recapitulates human NNK and NNAL bioactivation. These results provide guidance for the future use of these models in investigating lung carcinogenesis and developing preventive agents.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13248556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147959742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of P450 enzymes of the Cyp2abfgs gene subfamilies in tobacco smoke-induced lung tumorigenesis in mice.","authors":"Lisa M Tran, Patricia C Edwards, Weizhu Yang, Qing-Yu Zhang, Weiguo Han, Nataliia Kovalchuk, Liang Ding, Xiangmeng Wu, Xiaoyu Fan, Angel Arredondo, Robin Jordan Agustin Merluza, David G Besselsen, J Rachel Reader, Laura S Van Winkle, Xinxin Ding","doi":"10.1093/carcin/bgag017","DOIUrl":"10.1093/carcin/bgag017","url":null,"abstract":"<p><p>Many chemical carcinogens in tobacco smoke require bioactivation by cytochrome P450 enzymes. While the roles of P450 enzymes in carcinogenesis have been demonstrated in vivo using several individual carcinogens at relatively high doses, no data has been reported on their contributions to carcinogenesis induced by tobacco smoke, a complex mixture of >4000 compounds. The present study aims to address this important knowledge gap, using mice deficient in the expression of enzymes of the Cyp2abfgs gene subfamilies, which are known to bioactivate multiple chemical carcinogens in tobacco smoke. Male and female wild-type (WT) and Cyp2abfgs-null mice on the A/J genetic background were exposed to environmental tobacco smoke (ETS), a mixture of mainstream and sidestream smoke, for 6 hours/day, 5 days/week, for 5 months, at a target dose of 0 or 120 mg/m3 suspended total particulate matter. All mice were returned to filtered air (FA) for 4 months after cessation of ETS exposure. At approximately 11 months of age, mice were euthanized, and lungs were collected for tumor enumeration. ETS exposure increased tumor multiplicity (number of tumors per lung) in WT mice by 2.5-fold (p<0.0001), but only by 1.7-fold in Cyp2abfgs-null mice (p<0.001), compared to FA-exposed mice (n=∼180 per group, male and female). Multiplicity of ETS-induced tumors was significantly reduced (by 50%; p<0.01) in Cyp2abfgs-null relative to WT mice. These results demonstrate for the first time, in vivo, that bioactivation of ETS constituents by P450 enzymes, of the Cyp2abfgs gene subfamilies, play an important role in tobacco-smoke induced lung tumorigenesis in mice.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147484757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adverse events and recent advances in CAR-T-cell therapy.","authors":"Zhimin Bai, Xiaoyu Huang, Hui Jia, Zenghua Lin, Hong Liu","doi":"10.1093/carcin/bgaf083","DOIUrl":"10.1093/carcin/bgaf083","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR-T) cell therapy has been widely used in haematological malignancies and has achieved remarkable results. However, two major toxicities of CAR-T-cell therapy, cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, have been reported in many studies and often require hospitalization. There is evidence that CAR-T-cell therapy is being increasingly used clinically, so it is important to pay attention to its serious adverse events that may be life-threatening. In this review, we provide a detailed discussion of the clinical manifestations, classification, risk factors, and management and treatment of serious adverse events to provide theoretical support for clinicians to manage such cases. Although the clinical application of CAR-T cells continues to expand, adverse events associated with CAR-T-cell therapy are inevitable. With the identification of risk factors and the application of various new therapeutic approaches, the incidence and severity of these adverse events can be effectively controlled.</p>","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}