Genes and Environment最新文献

{"title":"Formation of the toxic furan metabolite 2-butene-1,4-dial through hemin-induced degradation of 2,4-alkadienals in fried foods.","authors":"Hiroshi Kasai, Kazuaki Kawai, Koichi Fujisawa","doi":"10.1186/s41021-025-00330-2","DOIUrl":"https://doi.org/10.1186/s41021-025-00330-2","url":null,"abstract":"<p><strong>Background: </strong>The mechanism of protein modification by 2,4-alkadienals (ADE), lipid peroxidation products prevalent in fried foods, was investigated through model reactions.</p><p><strong>Results: </strong>A mixture of 2,4-heptadienal (HDE) and hemin was initially incubated at pH 3.0-7.4, followed by treatment with acetyl-cysteine (AcCys) and acetyl-lysine (AcLys) at pH 7.4. Analysis via HPLC revealed a product with a characteristic UV spectrum as the primary peak. This product was identified as an AcCys-pyrrole-AcLys (CPL) crosslink derived from AcCys, 2-butene-1,4-dial (BDA), and AcLys. Increasing the HDE concentration in the initial reaction led to maximum CPL formation at pH 3.5 in the presence of hemin. Lowering the HDE concentration with a higher Cys/HDE ratio resulted in CPL formation, which was observed at pH 7.4 and 3.5 in the presence of hemin. Upon incubation of ADE and hemin at pH 3.0-3.5, BDA was directly identified as 2,4-dinitrophenylhydrazone. BDA was also detected in the 2,4-decadienal reaction mixture. Additionally, a notable propensity for high BDA-dC adduct formation with hemin under acidic conditions was observed, consistent with the results of CPL assay and BDA-2,4-dinitrophenylhydrazone analysis.</p><p><strong>Conclusions: </strong>1) BDA is efficiently generated from ADE in the presence of hemin under gastric conditions, and 2) BDA-derived CPL can also form under physiological conditions (pH 7.4) through the interaction of ADE, hemin, Cys, and Lys. BDA is recognized as the primary reactive metabolite of the suspected carcinogen furan (IARC, 2B). Given that human intake of ADE exceeds that of furan and acrylamide (IARC 2A) by several orders of magnitude, and the estimated hemin concentration in the stomach post-meal is comparable to the present study, a substantial amount of BDA may form in the stomach following consumption of fried foods and meat. The risk assessment of ADE warrants a thorough re-evaluation, based on the toxicity mechanism of BDA.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"8"},"PeriodicalIF":2.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of TDP2 in the repair of DNA damage induced by the radiomimetic drug Bleomycin.","authors":"Naoto Shimizu, Kazuki Izawa, Mubasshir Washif, Ryosuke Morozumi, Kouji Hirota, Masataka Tsuda","doi":"10.1186/s41021-025-00329-9","DOIUrl":"https://doi.org/10.1186/s41021-025-00329-9","url":null,"abstract":"<p><strong>Background: </strong>Bleomycin (Bleo) is a glycopeptide with potent antitumor activity that induces DNA double-strand breaks (DSBs) through free radical generation, similar to ionizing radiation (IR). Therefore, Bleo is considered a radiomimetic drug. However, differences in DNA repair mechanisms between IR- and Bleo-induced DNA damage have not been fully elucidated. Therefore, in the present study, we examined a panel of repair-deficient human TK6 cell lines to elucidate the relative contributions of individual repair factors.</p><p><strong>Results: </strong>Our comprehensive profiling indicated that both non-homologous end joining (NHEJ) and homologous recombination (HR) contributed to DSB repair induced by X-rays and Bleo. Furthermore, tyrosyl-DNA phosphodiesterase (TDP)-related repair was a significant factor for cellular sensitivity to Bleo treatment. TDP1^-/-/TDP2^-/- cells exhibited greater sensitivity to Bleo than TDP1^-/- or TDP2^-/- cells, but not to X-rays. In addition, we determined whether TDP2 is involved in the repair of Bleo-induced DSBs using a neutral comet assay. In TDP1-deficient cells, knockout of TDP2 resulted in a significant delay in the repair kinetics of DSBs induced by Bleo, but not by X-rays.</p><p><strong>Conclusions: </strong>The contribution of the TDP-related pathway to DSB repair significantly differed between IR and radiomimetic drugs. The discovery of this novel TDP2-dependent repair of DSBs resulting from radiomimetic drug exposure indicates that TDP1 and TDP2 inhibition in combination with radiomimetic drugs represents a strategy for cancer treatment.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"7"},"PeriodicalIF":2.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The new era shaped by environmental genome monitoring - symposium of the japanese environmental mutagen and genome society (JEMS), 2024.","authors":"Hiroshi Honda, Takayoshi Suzuki, Masaaki Kitajima, Natsuko Ito Kondo, Kaede Miyata, Shunsuke Utsumi, Masami Yamada","doi":"10.1186/s41021-025-00327-x","DOIUrl":"10.1186/s41021-025-00327-x","url":null,"abstract":"<p><p>The symposium \"The New Era Shaped by Environmental Genome Monitoring,\" held in December 2024 by the Japanese Environmental Mutagen and Genome Society (JEMS), aimed to explore the interdisciplinary collaborations that are essential for the development of new scopes in environmental genome monitoring. This event highlighted the necessity of integrating mutagenicity research with ecological assessments to enhance public health and biodiversity conservation. Presentations focused on the evolving landscape of environmental genomics, including metagenomic analyses for antibiotic resistance, viral genomic surveillance in wastewater, and innovations in noninvasive biodiversity and stress monitoring through environmental DNA and RNA. This report summarizes the key discussions and presentations from the symposium, underscoring the critical role of environmental genome monitoring in shaping future safety research.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"6"},"PeriodicalIF":2.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Environmental factors in gastric carcinogenesis and preventive intervention strategies.","authors":"Yuzhi Tan, Juntaro Matsuzaki, Yoshimasa Saito, Hidekazu Suzuki","doi":"10.1186/s41021-025-00328-w","DOIUrl":"10.1186/s41021-025-00328-w","url":null,"abstract":"<p><p>Gastric cancer, a significant global health concern, arises from a complex interplay of genetic and environmental factors. Helicobacter pylori (H. pylori) infection is a major risk factor that can be mitigated through eradication strategies. Epstein-Barr virus (EBV) infection causes a distinct subtype of gastric cancer called EBV-associated gastric cancer. The gastric microbiome, a dynamic ecosystem, is also involved in carcinogenesis, particularly dysbiosis and specific bacterial species such as Streptococcus anginosus. Long-term use of proton pump inhibitors and potassium-competitive acid blockers also increases the risk of gastric cancer, whereas non-steroidal anti-inflammatory drugs including aspirin may have a protective effect. Smoking significantly increases the risk, and cessation can reduce it. Dietary factors such as high intake of salt, processed meats, and red meat may increase the risk, whereas a diet rich in fruits and vegetables may be protective. Extracellular vesicles, which are small membrane-bound structures released by cells, modulate the tumor microenvironment and may serve as biomarkers for risk stratification and as therapeutic targets in gastric cancer. This review highlights the multifaceted etiology of gastric cancer and its risk factors and emphasizes the importance of a multi-pronged approach to prevention including H. pylori eradication and modification of lifestyle factors, as well as the potential of microbiome-based and EV-based interventions. Further research is needed to refine risk stratification and to develop personalized prevention strategies.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"5"},"PeriodicalIF":2.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer prevention: past challenges and future directions.","authors":"HeeKyung Seong, Runa Izutsu, Mitsuhiko Osaki, Futoshi Okada","doi":"10.1186/s41021-025-00326-y","DOIUrl":"10.1186/s41021-025-00326-y","url":null,"abstract":"<p><p>Almost 70 years have passed since the molecular mechanism of carcinogenesis was hypothesized to involve multiple gene mutations. More than 1,000 cancer-related genes, including oncogenes and tumor suppressor genes, accelerate carcinogenesis by altering molecular functions and gene expression through mutations and epigenetic changes and have been shown to cause multistep carcinogenesis in several organ cancers. The elucidation of cancer-related gene abnormalities has led to the development of molecular-targeted therapies that focus on driver molecules, known as precision medicine, in addition to conventional treatments such as surgery, radiotherapy, and chemotherapy. Now that the mechanism of cancer development has been largely elucidated, options for cancer treatment and its outcomes have improved, and cancer research is moving to the next stage: cancer prevention. Cancer prevention using chemicals was first proposed approximately 50 years ago. It is the concept of stabilizing, arresting, or reverting precancerous lesions to normal tissues using synthetic vitamin A analogs (retinoids). Cancer chemoprevention is now considered to consist of three elements: \"primary prevention,\" which prevents the development of tumors and prevents benign tumors converting into more malignant ones; \"secondary prevention,\" which aims for early detection through cancer screening and treatment; and \"tertiary prevention,\" which reduces the risk of recurrence and extends the time until death from cancer through treatment. Consequently, there is no clear boundary between the prevention and treatment strategies. Therefore, chemoprevention targets the entire process, from normal cells to precancerous lesions, malignant progression of tumors, and death by cancer. Basic and clinical research has revealed that cancer prevention is influenced by race, regional, and national differences, as well as individual differences such as genetic factors, environmental factors, and lifestyle habits. This review provides an overview of the progress made in cancer prevention and summarizes future directions.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"4"},"PeriodicalIF":2.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"History of the Organisation for Economic Co-operation and Development (OECD) test guidelines for non-animal test methods in Japan.","authors":"Hajime Kojima","doi":"10.1186/s41021-024-00323-7","DOIUrl":"10.1186/s41021-024-00323-7","url":null,"abstract":"<p><p>The number of alternatives to animal tests (non-animal test methods) for human health developed globally account for more than 40% of the test methods in the Organisation for Economic Co-operation and Development (OECD) Guidelines for the Testing of Chemicals (TGs). Within the TGs, the National Institute of Health Sciences (NIHS) has standardized 16 OECD TGs for human health, implemented four major revisions, and developed one test method for the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S10 guidelines on photosafety. This review describes trends in the OECD and Japan that mainly focus on international standardizations of non-animal test methods for human health. Drawing from this experience, I hope Japan will advance new approach methodologies for detecting systemic toxicity, which are in global demand.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"3"},"PeriodicalIF":2.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased matrix metalloproteinase-1 expression by coexposure to UVA and cigarette sidestream smoke and contribution of histone acetylation.","authors":"Ryoma Ito, Yukako Komaki, Yuko Ibuki","doi":"10.1186/s41021-025-00325-z","DOIUrl":"10.1186/s41021-025-00325-z","url":null,"abstract":"<p><strong>Background: </strong>Skin is exposed to various environmental factors throughout life, and some of these factors are known to contribute to skin aging. Long-term solar UV exposure is a well-known cause of skin aging, as is cigarette smoke, which contains a number of chemicals. In this study, combined effect of UVA and cigarette sidestream smoke (CSS) on matrix metalloproteinase-1 (MMP-1) induction was investigated. MMP-1 is the main protease that initiates collagen type I fiber fragmentation in human skin and is associated with aging.</p><p><strong>Results: </strong>Combined exposure to UVA and CSS enhanced MMP-1 induction, accompanied by collagen type I (COL1A1) gene suppression. The basal expression of MMP-1 was higher in senescent cells than in normal cells, with a pronounced increase after coexposure to UVA and CSS. UVA irradiation resulted in global histone H3 acetylation, and we considered this was responsible for the MMP-1 upregulation. Histone deacetylase inhibitors, sodium acetate, propionate, and butyrate, all enhanced the CSS-induced MMP-1 according to the degree of histone acetylation.</p><p><strong>Conclusion: </strong>These results suggest that UVA and CSS additively induce MMP-1, which may lead to skin aging, and that such combined effect may further promote aging in aged skin. UVA-induced histone acetylation may contribute to MMP-1 induction.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"2"},"PeriodicalIF":2.7,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11765920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diurnal and daily fluctuations in levels of the urinary oxidative stress marker 8-hydroxyguanosine in spot urine samples.","authors":"Yun-Shan Li, Koichi Fujisawa, Kazuaki Kawai","doi":"10.1186/s41021-025-00324-0","DOIUrl":"10.1186/s41021-025-00324-0","url":null,"abstract":"<p><strong>Background: </strong>Urinary 8-hydroxyguanosine (8-OHGuo) levels serve as a biomarker for oxidative stress and hydroxyl radical-induced RNA damage. Evaluating the diurnal and daily fluctuations in urinary 8-OHGuo excretion levels is essential for understanding its implications. However, research in this area remains limited. In this study, we aim to investigate the diurnal and daily fluctuations in 8-OHGuo levels as well as the factors that influence these variations, using spot urine samples.</p><p><strong>Methods: </strong>Urine samples were collected from seven healthy participants during each urination from the time of awakening until 24:00 h to evaluate diurnal variations. To assess daily fluctuations, urine samples were collected from 18 healthy participants at the time of awakening for 23 consecutive days. The urinary 8-OHGuo levels were measured using an HPLC-ECD method.</p><p><strong>Results: </strong>No significant variations were observed in the diurnal levels of urinary 8-OHGuo among non-smokers. Conversely, the daily variation of 8-OHGuo in the urine of the smoker was significant, with a coefficient of variation of 18.71%. Each individual maintained a characteristic value despite some diurnal fluctuations. Furthermore, the daily levels of 8-OHGuo exhibited a range of variations influenced by lifestyle factors, including mental state, sleep duration, smoking, menstrual cycle, and dietary habits.</p><p><strong>Conclusion: </strong>As a specific marker of RNA oxidation, 8-OHGuo provides unique insights distinct from those provided by the widely used DNA oxidation marker 8-hydroxydeoxyguanosine as an indicator of oxidative stress. Urinary 8-OHGuo could serve as a valuable biomarker for managing and preventing oxidative stress-related diseases, provided that the specific range of daily variations is established. The high daily variation in urinary 8-OHGuo levels necessitates the use of multiple samples to accurately determine individual levels. However, further research with large sample sizes will help to validate these findings.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"47 1","pages":"1"},"PeriodicalIF":2.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Four functional genotoxic marker genes (Bax, Btg2, Ccng1, and Cdkn1a) discriminate genotoxic hepatocarcinogens from non-genotoxic hepatocarcinogens and non-genotoxic non-hepatocarcinogens in rat public toxicogenomics data, Open TG-GATEs.","authors":"Chie Furihata, Takayoshi Suzuki","doi":"10.1186/s41021-024-00322-8","DOIUrl":"10.1186/s41021-024-00322-8","url":null,"abstract":"<p><strong>Background: </strong>Previously, Japanese Environmental Mutagen and Genome Society/Mammalian Mutagenicity Study Group/Toxicogenomics Study Group (JEMS/MMS toxicogenomic study group) proposed 12 genotoxic marker genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2, and Tubb4b) to discriminate genotoxic hepatocarcinogens (GTHCs) from non-genotoxic hepatocarcinogens (NGTHCs) and non-genotoxic non-hepatocarcinogens (NGTNHCs) in mouse and rat liver using qPCR and RNA-Seq and confirmed in public rat toxicogenomics data, Open TG-GATEs, by principal component analysis (PCA). On the other hand, the U.S. Environmental Protection Agency (US EPA) suggested seven genotoxic marker genes (Bax, Btg2, Ccng1, Cgrrf1, Cdkn1a, Mgmt, and Tmem47) with Open TG-GATEs data. Four genes (Bax, Btg2, Ccng1, and Cdkn1a) were common in these two studies. In the present study, we examined the performance of these four genes in Open TG-GATEs data using PCA.</p><p><strong>Results: </strong>The study's findings are of paramount significance, as these four genes proved to be highly effective in distinguishing five typical GTHCs (2-acetylaminofluorene, aflatoxin B1, 2-nitrofluorene, N-nitrosodiethylamine and N-nitrosomorpholine) from seven typical NGTHCs (clofibrate, ethanol, fenofibrate, gemfibrozil, hexachlorobenzene, phenobarbital, and WY-14643) and 11 NGTNHCs (allyl alcohol, aspirin, caffeine, chlorpheniramine, chlorpropamide, dexamethasone, diazepam, indomethacin, phenylbutazone, theophylline, and tolbutamide) by PCA at 24 h after a single administration with 100% accuracy. These four genes also effectively distinguished two typical GTHCs (2-acetylaminofluorene and N-nitrosodiethylamine) from seven NGTHCs and ten NGTNHCs by PCA on 29 days after 28 days-repeated administrations, with a similar or even better performance compared to the previous 12 genes. Furthermore, the study's analysis revealed that the three intermediate GTHC/NGTHCs (methapyrilene, monocrotaline, and thioacetamide, which were negative in the Salmonella test but positive in the in vivo rat liver test) were located in the intermediate region between typical GTHCs and typical NGTHCs by PCA.</p><p><strong>Conclusions: </strong>The present results unequivocally demonstrate the availability of four genotoxic marker genes ((Bax, Btg2, Ccng1, and Cdkn1a) and PCA in discriminating GTHCs from NGTHCs and NGTNHCs in Open TG-GATEs. These findings strongly support our recommendation that future rat liver in vivo toxicogenomics tests prioritize these four genotoxic marker genes, as they have proven to be highly effective in discriminating between different types of hepatocarcinogens.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"46 1","pages":"28"},"PeriodicalIF":2.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GATA1 activates HSD17B6 to improve efficiency of cisplatin in lung adenocarcinoma via DNA damage.","authors":"Xingxing Shao, Hailang Hou, Huijie Chen, Wan Xia, Xinpu Geng, Jindao Wang","doi":"10.1186/s41021-024-00321-9","DOIUrl":"10.1186/s41021-024-00321-9","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) is the most common histological type of non-small cell lung cancer (NSCLC). Platinum-based chemotherapy, such as cisplatin chemotherapy, is the cornerstone of treatment for LUAD patients. Nevertheless, cisplatin resistance remains the key obstacle to LUAD treatment, for its mechanism has not been fully elucidated.</p><p><strong>Methods: </strong>HSD17B6 mRNA expression data were accessed from TCGA-LUAD database and differential expression analysis was performed. Enrichment analysis of HSD17B6 was conducted by GSEA, and its upstream transcription factors were predicted by hTFtarget. mRNA and protein expression levels of HSD17B6 and GATA1 were assayed by qRT-PCR and WB, and the binding relationship between them was verified by chromatin immunoprecipitation assay and dual luciferase reporter assay. Cell viability and IC₅₀ value of cisplatin-treated cells were measured by cell counting kit-8 assay. Cell cycle was assayed by flow cytometry. DNA damage level and DNA damage marker γ-H2AX expression were assayed by comet assay and western blot, respectively.</p><p><strong>Results: </strong>HSD17B6 was lowly expressed in LUAD tissues and cells and mainly enriched in homologous recombination and mismatch repair pathways. As cell function experiments revealed, overexpression of HSD17B suppressed malignant phenotypes and cisplatin resistance in LUAD cells through DNA damage. Bioinformatics analysis revealed that GATA1 is the upstream regulator of HSD17B6, which was markedly reduced in LUAD tissues and cells. ChIP and dual luciferase reporter assays ascertained the binding of GATA1 to HSD17B6. Knockdown of GATA1 attenuated the effect of overexpression of HSD17B6 on LUAD cell behaviors and cisplatin resistance.</p><p><strong>Conclusion: </strong>Transcription factor GATA1 could activate HSD17B6 to inhibit cisplatin resistance in LUAD through DNA damage, suggesting that GATA1/HSD17B6 axis may be a potential therapeutic target for chemotherapy resistance in LUAD patients.</p>","PeriodicalId":12709,"journal":{"name":"Genes and Environment","volume":"46 1","pages":"27"},"PeriodicalIF":2.7,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11654308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}