Carcinogenesis最新文献_第10页

SRSF3 knockdown-induced cellular senescence as a possible therapeutic strategy for non-small cell lung cancer. SRSF3敲低诱导细胞衰老作为非小细胞肺癌的可能治疗策略

IF 3.8 3区医学

Carcinogenesis Pub Date : 2025-11-21 DOI: 10.1093/carcin/bgaf082

Shinji Nakamichi, Natalia von Muhlinen, Leo Yamada, Jilian R Melamed, Tyler E Papp, Hamideh Parhiz, Drew Weissman, Izumi Horikawa, Curtis C Harris

{"title":"SRSF3 knockdown-induced cellular senescence as a possible therapeutic strategy for non-small cell lung cancer.","authors":"Shinji Nakamichi, Natalia von Muhlinen, Leo Yamada, Jilian R Melamed, Tyler E Papp, Hamideh Parhiz, Drew Weissman, Izumi Horikawa, Curtis C Harris","doi":"10.1093/carcin/bgaf082","DOIUrl":"10.1093/carcin/bgaf082","url":null,"abstract":"Tyrosine kinase (TK) inhibitors improve clinical outcomes in non-small cell lung cancer (NSCLC) with targetable mutations. However, such NSCLC cases account for only about 50% in the western populations. Inhibition of the splicing factor SRSF3 has been reported to be tumor-suppressive in other cancer cell types. This study for the first time explores the tumor-suppressive activity of siRNA knockdown of SRSF3 in NSCLC cells. The cell lines used were A549 (no TK mutation; TP53 wild type), NCI-H1975 (EGFR L858R/T790M; TP53 R273H mutant), NCI-H322 (no TK mutation; TP53 R248L mutant), and NCI-H596 (no TK mutation; TP53 G245C mutant). In all these cell lines, SRSF3 knockdown increased cellular senescence, as indicated by increased senescence-associated β-galactosidase activity and reduced cell proliferation. In A549 cells, increased apoptotic cleavage of caspase-3 and poly(ADP-ribose) polymerase was also observed. A tumor-suppressive p53 isoform, p53β, was shown to be upregulated by SRSF3 knockdown. However, overexpression of p53β did not induce cellular senescence or apoptosis, suggesting that this p53 isoform is not a primary effector of SRSF3 knockdown in NSCLC cells. Gene expression analyses suggested that the SRSF3 knockdown-induced senescence in NSCLC cells may be mediated by the downregulation of TOP2A, UBE2C, or ASPM, which are known oncogenic factors associated with poor patient prognosis. We also generated SRSF3 siRNA-encapsulating lipid nanoparticles as a future therapeutic tool. This study proposes a therapeutic strategy for NSCLC that is independent of the mutation status of TP53 and TK-encoding genes.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12629605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502150","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}

引用次数: 0

The Oncogenic Role of AURKA in Gastric Cancer: Mechanisms, Pathways, and Clinical Relevance. AURKA在胃癌中的致癌作用：机制、途径和临床相关性。

IF 2.9 3区医学

Carcinogenesis Pub Date : 2025-09-09 DOI: 10.1093/carcin/bgaf054

Caixia Lv, Yan Liu, Huanhu Zhang

{"title":"The Oncogenic Role of AURKA in Gastric Cancer: Mechanisms, Pathways, and Clinical Relevance.","authors":"Caixia Lv, Yan Liu, Huanhu Zhang","doi":"10.1093/carcin/bgaf054","DOIUrl":"https://doi.org/10.1093/carcin/bgaf054","url":null,"abstract":"Aurora kinase A (AURKA) is a serine/threonine kinase that plays a critical role in cell cycle regulation, particularly during mitosis. Recent studies have identified AURKA as an oncogene overexpressed in various cancers, including gastric cancer (GC). This review summarizes the molecular mechanisms by which AURKA contributes to GC pathogenesis, including its roles in cell proliferation, apoptosis inhibition, epithelial-mesenchymal transition (EMT), and cancer stemness. AURKA regulates key signaling pathways such as PI3K/Akt, Wnt/β-catenin, NF-κB, and JAK2/STAT3, promoting tumor growth, metastasis, and therapy resistance. Additionally, AURKA interacts with critical tumor suppressors like p53 and PTEN, further enhancing its oncogenic potential. Clinical studies have demonstrated that AURKA overexpression correlates with poor prognosis in GC patients, highlighting its potential as a diagnostic and therapeutic target. This review also discusses the efficacy of AURKA inhibitors in preclinical settings, offering insights into their therapeutic potential. By elucidating the multifaceted roles of AURKA in GC, this review aims to provide a comprehensive understanding of its mechanisms and implications for future research and treatment strategies.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022907","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}

引用次数: 0

Pathological point of view on the atomic bomb-related solid cancers. 原子弹相关实体癌的病理学观点。

IF 3.8 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf072

Masahiro Nakashima, Hirokazu Kurohama, Yuko Akazawa

{"title":"Pathological point of view on the atomic bomb-related solid cancers.","authors":"Masahiro Nakashima, Hirokazu Kurohama, Yuko Akazawa","doi":"10.1093/carcin/bgaf072","DOIUrl":"10.1093/carcin/bgaf072","url":null,"abstract":"Eighty years have passed since the atomic bombings (A-bombing) of Hiroshima and Nagasaki in August 1945. Survivors represent an unparalleled and irreplaceable human cohort for comprehensively studying the long-term carcinogenic effects of radiation exposure. This review provides a pathological perspective on A-bomb radiation-related solid cancers. Key findings underscore the persistent nature of radiation-induced carcinogenesis: an increased risk of solid cancers has been evident for over 10 years post-bombing and continues to persist. Epidemiological data consistently demonstrate a linear dose-response relationship, with the risk of all solid cancers increasing by ∼40%-50% per Gy, notably without an apparent threshold. The phenomenon of multiple primary cancers is significantly affected by A-bomb radiation, suggesting a systemic predisposition. At a molecular level, evidence points to long-lasting genomic instability, characterized by constitutive activation of the DNA damage response in non-neoplastic epidermis of proximally exposed survivors. This persistent genomic disruption is a critical contributing factor to tumorigenesis. Furthermore, radiation-associated cancers exhibit distinct molecular features. For instance, specific gene fusions are prevalent in thyroid cancer, while HER2 and c-MYC co-amplifications are observed in breast cancer, and gene expression alterations are noted in gastric cancer, often differing from sporadic cases. Research into biomarkers, such as cdkn1a in a rat model of thyroid carcinogenesis, shows promise for identifying radiation effects from the early pre-cancerous phase. This comprehensive analysis highlights the profound and enduring impact of A-bomb radiation on human carcinogenesis. The insights derived from this unique cohort are profoundly relevant for understanding and mitigating global radiation health risks.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":"46 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145548503","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}

引用次数: 0

Eighty years of cancer research after the atomic bombings of Hiroshima and Nagasaki. 广岛和长崎原子弹爆炸后80年的癌症研究。

IF 3.8 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf071

Jonathan M Samet, Preetha Rajaraman, Sharon R Pine, Tatsuhiro Shibata

引用次数: 0

The importance of data from the atomic bomb survivors for international radiological protection. 原子弹幸存者数据对国际辐射防护的重要性。

IF 3.8 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf062

Richard Wakeford, Dominique Laurier

{"title":"The importance of data from the atomic bomb survivors for international radiological protection.","authors":"Richard Wakeford, Dominique Laurier","doi":"10.1093/carcin/bgaf062","DOIUrl":"10.1093/carcin/bgaf062","url":null,"abstract":"Epidemiological studies using data from the lifetime experience of the survivors of the atomic bombings of Japan have been fundamental in shaping the international system of radiological protection since a clear excess risk of, first leukaemia and then other cancers, became apparent in the 1950s and 1960s. Cancer mortality and incidence data have been collected, collated and analysed by the Radiation Effects Research Foundation (RERF, and its predecessor, the Atomic Bomb Casualty Commission, ABCC) and the risk estimates so produced have been used subsequently by the International Commission on Radiological Protection (ICRP) to provide the main technical basis of its general recommendations, from its 1965 Recommendations to the latest 2007 Recommendations. As the database has grown with increasing follow-up of the survivors, together with continued refinement of the dosimetry system, ABCC/RERF analyses have become more sophisticated, permitting knowledge of the variation of risks for a growing number of specific types of cancer, as modified by sex, age-at-exposure and time-since-exposure/attained age. A growing database of non-cancer effects, such as diseases of the circulatory system and eye lens opacities, is also providing risk estimates. Even now, 80 years after the bombings, the survivors provide important information on risks decades after exposure at a young age. There is little doubt that recent RERF studies of cancer and non-cancer diseases in the survivors will continue to steer the ICRP in its progress towards the next Recommendations.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":"46 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12558147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145376098","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}

引用次数: 0

Empowering the next generation of radiation research fueled by international collaboration. 在国际合作的推动下，加强下一代辐射研究。

IF 2.9 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf077

Jiro Ezaki, Cato M Milder, Shona R Elgart, Shintaro Ishii, Ryuichiro Sano, Hiroyuki Tanaka, Yuta Tsukumo, Joey Y Zhou, Masato Yasuda, Michael J Silverman, Hitomi Hori

引用次数: 0

FZD6 promotes 5-fluorouracil resistance through inhibiting pyroptosis in colorectal cancer. FZD6通过抑制结直肠癌焦亡促进5-氟尿嘧啶耐药。

IF 3.8 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf041

Zilong He, Jing Yang, Yu Zhang, TongXin Zhang, Tao Guo, Linfang Jin, Yong Mao, Teng Wang

{"title":"FZD6 promotes 5-fluorouracil resistance through inhibiting pyroptosis in colorectal cancer.","authors":"Zilong He, Jing Yang, Yu Zhang, TongXin Zhang, Tao Guo, Linfang Jin, Yong Mao, Teng Wang","doi":"10.1093/carcin/bgaf041","DOIUrl":"10.1093/carcin/bgaf041","url":null,"abstract":"Resistance to 5-fluorouracil (5-FU) causes treatment failure in most colorectal cancer (CRC) cases. Pyroptosis is associated with chemotherapy resistance, although its role in 5-FU resistance in CRC is not well understood. To investigate this, we performed proteomic sequencing and bioinformatics analysis on wild-type and 5-FU-resistant CRC cell lines. Subsequently, Frizzled receptor 6 (FZD6) knockdown and overexpression cell lines were established using a lentiviral system. CCK-8, colony formation, and EdU assays were performed to assess the viability and proliferative potential of 5-FU-treated cells. The morphological changes associated with pyroptosis were examined by microscopic imaging and electron microscopy. The nuclear expression of β-catenin was examined by immunofluorescence and western blotting. These findings indicated that FZD6 protein was upregulated in the 5-FU-resistant CRC cells compared with the corresponding wild-type cell lines, an observation further validated through immunohistochemical analysis of clinical samples. Additionally, 5-FU treatment induced NLRP3/caspase-1/GSDMD-mediated classical pyroptosis in the wild-type CRC cells and decreased their viability, while the pyroptosis inhibitor Ac-FITD-CMK enhanced drug resistance. Furthermore, overexpression of FZD6 promoted nuclear translocation of β-catenin, reduced pyroptosis, and increased 5-FU resistance. In contrast, 5-FU treatment did not induce significant pyroptosis in drug-resistant cells, while pyroptosis inducers (nigericin or LPS + ATP) significantly reduced cell viability regardless of 5-FU. Moreover, knockdown of FZD6 decreased nuclear translocation of β-catenin, enhanced pyroptosis, and reduced 5-FU resistance. Finally, β-catenin knockdown enhanced pyroptosis and decreased 5-FU resistance. Thus, FZD6 promotes 5-FU resistance in CRC cells by inhibiting pyroptosis through increased nuclear translocation of β-catenin.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854613","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}

引用次数: 0

Epithelial Ikkβ deletion modulates immune responses and the IFNγ/CXCL9 axis during early esophageal carcinogenesis. 在早期食管癌发生过程中，上皮Ikkβ缺失调节免疫反应和IFNγ/CXCL9轴。

IF 3.8 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf055

Nathan Hodge, Marie-Pier Tétreault

{"title":"Epithelial Ikkβ deletion modulates immune responses and the IFNγ/CXCL9 axis during early esophageal carcinogenesis.","authors":"Nathan Hodge, Marie-Pier Tétreault","doi":"10.1093/carcin/bgaf055","DOIUrl":"10.1093/carcin/bgaf055","url":null,"abstract":"Esophageal cancer is a major cause of cancer-related death, often preceded with chronic inflammation and injuries. The NFκB/IKKβ pathway plays a central role in inflammation, yet its role in early esophageal carcinogenesis remains unclear. This study investigated the role of epithelial IKKβ in early esophageal carcinogenesis. Mice were treated with the carcinogen 4-nitroquinoline-1-oxide (4-NQO) or a vehicle for one month to induce precancerous lesions. Esophagi were harvested and examined through histological, protein, flow cytometry, and RNA analyses. Histological analysis revealed that 4-NQO treatment led to increased inflammation, intraepithelial CD45+ immune cells, and elevated IKKβ phosphorylation levels. Mice with esophageal epithelial-specific Ikkβ deletion (4-NQO/IkkβEEC-KO) showed delayed progression to a precancerous state, with reduced immune cell recruitment compared to 4-NQO/controls. Immunophenotyping showed decreased recruitment of T cells, including CD4+, CD8+ and regulatory (Tregs) T cells, and increased recruitment of macrophages in 4-NQO/IkkβEEC-KO mice compared with 4-NQO/controls. RNA sequencing data identified 262 differentially expressed genes in 4-NQO/IkkβEEC-KO mice, implicating pathways related to inflammation and wound healing. Notably, the chemokine CXCL9, a T cell chemoattractant, was significantly upregulated in 4-NQO control mice, but not in 4-NQO/IkkβEEC-KO mice. Further analysis identified IFNγ as an upstream regulator of Cxcl9 expression, and neutralization of IFNγ reduced Cxcl9 expression levels in 4-NQO treated mice. Additionally, in vitro studies demonstrated that IFNγ upregulates Cxcl9 in an NFκB dependent manner in esophageal keratinocytes. These findings suggest that epithelial IKKβ regulates the immune microenvironment in early esophageal carcinogenesis through the IFNγ/CXCL9 axis and influencing T cell recruitment and inflammatory responses.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013749","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}

引用次数: 0

Genomic landscape of radiation-induced somatic mutations in a normal cell. 正常细胞中辐射诱导的体细胞突变的基因组景观。

IF 3.8 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf044

Yukiko Matsuda, Osamu Tanabe

{"title":"Genomic landscape of radiation-induced somatic mutations in a normal cell.","authors":"Yukiko Matsuda, Osamu Tanabe","doi":"10.1093/carcin/bgaf044","DOIUrl":"10.1093/carcin/bgaf044","url":null,"abstract":"Atomic bomb survivors have been found to have an excess risk of late adverse effects, including leukemia, various solid cancers, and non-cancer diseases, depending on the dose of radiation exposure. Radiation-induced DNA damage can lead to errors in DNA repair, resulting in the induction of somatic mutations in cells. Since these mutations are thought to contribute to an increased risk of radiation-induced carcinogenesis, various approaches, such as mutation analysis at specific genetic loci and chromosomal analysis, have been used to investigate their characteristics. However, previous methods were only capable of detecting a subset of radiation-induced mutations, making it difficult to quantitatively and comprehensively capture their specificity, including the mutation spectrum. Recently, whole-genome sequencing combined with of ex vivo single-cell culture has enabled a comprehensive analysis of radiation-induced mutations in individual cells. Such studies, including our own, have demonstrated that short, non-repeat deletions occurring outside of tandem repeats represent the most distinctive signature of radiation-induced mutagenesis, showing clear dose dependence and consistency across multiple tissues. Structural variants (excluding retroelement insertions) and multisite mutations also showed radiation specificity, albeit to a lesser extent and at a lower frequency than non-repeat deletions. These findings may offer insights into the molecular mechanisms underlying radiation-induced oncogenesis and non-cancer disease development.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":"46 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12558139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145376113","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}

引用次数: 0

History and current developments of RERF dosimetry. 反辐射剂量学的历史和当前发展。

IF 3.8 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf045

Harry M Cullings, Sachiyo Funamoto, Stephen D Egbert, Keith T Griffin, Colin J Paulbeck, Sean J Domal, Camilo M Correa-Alfonso, Shota Shimizu, Tatsuhiko Sato, Choonsik Lee, Akira Endo, Wesley E Bolch

{"title":"History and current developments of RERF dosimetry.","authors":"Harry M Cullings, Sachiyo Funamoto, Stephen D Egbert, Keith T Griffin, Colin J Paulbeck, Sean J Domal, Camilo M Correa-Alfonso, Shota Shimizu, Tatsuhiko Sato, Choonsik Lee, Akira Endo, Wesley E Bolch","doi":"10.1093/carcin/bgaf045","DOIUrl":"10.1093/carcin/bgaf045","url":null,"abstract":"Studies of the health effects among Japanese atomic bomb survivors, including radiation-induced carcinogenesis, necessitate accurate radiation dose estimates for individual survivors from the Hiroshima and Nagasaki bombings. Efforts toward this goal commenced shortly after the bombings in 1945, resulting in a series of dosimetry systems developed over the years to calculate survivor doses for a roster currently numbering 135 852 survivors. These systems estimate a survivor's dose based on data such as the survivor's location and shielding by structures such as houses. This paper focuses on a series of systems created over the years, first by US groups and later by binational US-Japan groups, with particular emphasis on the most recent dosimetry systems: Dosimetry System 2002 and DS02 Revision 1. Furthermore, we discuss the latest advancement, the J45 phantoms, which introduces a new system of anthropomorphic phantoms for calculations of dose to specific organs of the human body with consideration of body self-shielding and has been in development over the last few years.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":"46 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12558137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145376154","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}

引用次数: 0