Carcinogenesis最新文献

The regulation of gene expression through chromatin architecture plays a critical role in acute myeloid leukemia (AML). In this study, the influence of MAPK3 on CTCF-mediated chromatin interactions in AML was examined, focusing on gene regulation and chromatin architecture. Immunoprecipitation coupled with mass spectrometry (IP-MS) was conducted to identify CTCF-binding proteins in AML cell lines. Chromatin immunoprecipitation sequencing (ChIP-seq) was used to assess the impact of MAPK3 modulation on CTCF DNA binding, following treatment with an MAPK3 activator or inhibitor. Additionally, chromatin interactions were evaluated using 3C-qPCR, and specific enhancer sites at the SKAP2 locus were deleted using CRISPR-Cas9. Results demonstrated that IP-MS identified MAPK3 as a key CTCF-binding protein, indicating its potential role in AML chromatin regulation. MAPK3 significantly influences CTCF binding at distal intergenic regions upstream of SKAP2, as confirmed by ChIP-seq. Chromatin interaction analyses revealed that CTCF-regulated enhancer-promoter interactions at SKAP2 are modulated by MAPK3 activity. Furthermore, deletion of enhancer regions E4 and E6 led to decreased SKAP2 expression. These findings highlight the critical role of MAPK3 in regulating CTCF-mediated chromatin interactions and suggest that targeting MAPK3-regulated chromatin remodeling could be a novel therapeutic strategy for AML.

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.

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.

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.

The year 2025 marks the 80th anniversary of one of the worst human-caused tragedies: the atomic bombings of Hiroshima and Nagasaki, with acute death tolls of approximately 140,000 in Hiroshima and 74,000 in Nagasaki by the end of 1945. This editorial provides historical and social context for the articles in this special issue of Carcinogenesis.

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.

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.

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.

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.