Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis最新文献_第3页

Targeting cancer-cell mitochondria using Tigecycline improves radiotherapy response in colorectal cancer cell line 替加环素靶向肿瘤细胞线粒体改善结直肠癌细胞系放疗反应

IF 1.9 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis

Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2025.111905

Sepideh Hassanpour Khodaei , Shahnaz Sabetkam , Zeinab Mazloumi , Khadijeh Dizaji Asl , Ali Rafat

Background

Colorectal cancer (CRC) is the third most common cancer worldwide and causes more than 50,000 deaths in the United States each year. Due to the limited therapeutic options and poor prognosis in CRC, extensive research and development of novel therapeutic methods is essential. In this regard, the presence of cancer stem cells with unlimited division ability is the main reason for the therapeutic resistance in CRC. Tigecycline is a pharmacological mitochondria inhibitor and blocks mitochondria-related cell proliferation in cancer cells. This study investigated the effects of Tigecycline combined with radiotherapy on CRC cell apoptosis.

Methods

Human colorectal cancer cells (HCT-116) were treated with Tigecycline, and cell viability was measured with MTT assay. In the next step, the cells were exposed to radiation using a Siemens Primus 6 MV linear accelerator at radiation dose of 400 cGy. Finally, we evaluated cancer cell apoptosis, caspase-3 activity and apoptotic-related genes expression with AnnexinV/PI, flowcytometry and gene expression, respectively.

Results

The MTT assay revealed an IC50 value of 93 μM for Tigecycline after 48 hours. Mitochondria inhibition, at its IC50 value, sensitizes colorectal cancer cells to radiotherapy. Compared to monotherapy, the combination therapy increased the number of apoptotic cells and caspase-3 activity, up-regulated pro-apoptotic genes, and down-regulated anti-apoptotic genes.

Conclusion

In conclusion, our data suggests that targeting mitochondria may represent a clinically relevant approach to enhance the sensitivity of colorectal cancer cells to therapy. These findings could provide new insights into cancer therapy and might be used as a novel method to improve the current state of CRC therapy.

结直肠癌（CRC）是全球第三大常见癌症，每年在美国导致超过5万人死亡。由于结直肠癌的治疗选择有限，预后差，因此广泛研究和开发新的治疗方法至关重要。因此，具有无限分裂能力的肿瘤干细胞的存在是导致结直肠癌耐药的主要原因。替加环素是一种药理线粒体抑制剂，可阻断癌细胞中线粒体相关细胞的增殖。本研究探讨替加环素联合放疗对结直肠癌细胞凋亡的影响。方法替加环素处理人结直肠癌细胞（HCT-116），采用MTT法测定细胞活力。下一步，使用西门子Primus 6 MV线性加速器将细胞暴露在400 cGy的辐射剂量下。最后，我们分别用AnnexinV/PI、流式细胞术和基因表达法检测肿瘤细胞凋亡、caspase-3活性和凋亡相关基因的表达。结果MTT检测显示替加环素作用48 小时后的IC50值为93 μM。线粒体抑制，在其IC50值下，使结直肠癌细胞对放疗敏感。与单药治疗相比，联合治疗增加了凋亡细胞数量和caspase-3活性，上调了促凋亡基因，下调了抗凋亡基因。总之，我们的数据表明，靶向线粒体可能是提高结直肠癌细胞对治疗敏感性的临床相关方法。这些发现可能为癌症治疗提供新的见解，并可能作为改善CRC治疗现状的新方法。

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引用次数: 0

The complex development of psoralen-interstrand crosslink resistance in Escherichia coli requires AcrR inactivation, retention of a marbox sequence, and one of three MarA, SoxS, or Rob global regulators 在大肠杆菌中，补骨脂素-链间交联抗性的复杂发展需要AcrR失活、marbox序列的保留以及三种MarA、SoxS或Rob全球调控因子中的一种

IF 1.9 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis

Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2025.111898

Travis K. Worley , Ayah H. Asal, Lo Cooper, Charmain T. Courcelle, Justin Courcelle

Crosslinking agents, such as psoralen and UVA radiation, can be effectively used as antimicrobials and for treating several dysplastic conditions in humans, including some cancers. Yet, both cancer cells and bacteria can become resistant to these compounds, making it important to understand how resistance develops. Recently, several mutants were isolated that developed high levels of resistance to these compounds through upregulation of components of the AcrAB-TolC efflux pump. Here, we characterized these mutants and found that resistance specifically requires inactivating mutations of the acrR transcriptional repressor which also retain the marbox sequence found within this coding region. In addition, the presence of any one of three global regulators, MarA, SoxS, or Rob, is necessary and sufficient to bind to the marbox sequence and activate resistance. Notably, although psoralen is a substrate for the efflux pump, these regulators are not naturally responsive to this stress as neither psoralen, UVA, nor crosslink induction upregulates acrAB expression in the absence of mutation.

交联剂，如补骨脂素和UVA辐射，可以有效地用作抗菌剂和治疗人类的几种发育不良疾病，包括一些癌症。然而，癌细胞和细菌都可能对这些化合物产生耐药性，因此了解耐药性是如何产生的非常重要。最近，一些突变体被分离出来，它们通过上调acrabb - tolc外排泵的成分，对这些化合物产生了高水平的抗性。在这里，我们对这些突变体进行了表征，并发现抗性特异性地需要acrR转录抑制因子的失活突变，这些突变也保留了该编码区域内发现的marbox序列。此外，三种全局调控因子（MarA、SoxS或Rob）中的任何一种的存在都是与marbox序列结合并激活抗性的必要和充分条件。值得注意的是，尽管补骨脂素是外排泵的底物，但这些调节因子对这种应激没有自然反应，因为补骨脂素、UVA和交联诱导都不能在没有突变的情况下上调acrAB的表达。

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引用次数: 0

Genomic and molecular landscape of gallbladder cancer elucidating pathogenic mechanisms novel therapeutic targets and clinical implications 胆囊癌的基因组和分子景观阐明致病机制、新治疗靶点和临床意义。

IF 1.9 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis

Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2024.111896

Manishankar Kumar , Arun Kumar , Abhinav Srivastav , Ashok Ghosh , Dhruv Kumar

Gallbladder cancer (GBC) is an aggressive malignancy with a poor prognosis, often diagnosed at advanced stages due to subtle early symptoms. Recent studies have provided a comprehensive view of GBC's genetic and mutational landscape, uncovering crucial pathways involved in its pathogenesis. Environmental exposures, particularly to heavy metals, have been linked to elevated GBC risk. Established signaling pathways, including hormonal, apoptotic, metabolic, inflammatory, and DNA damage repair pathways, are integral to GBC progression, and evidence points to the involvement of specific germline and somatic mutations in its development. Key mutations in genes such as KRAS, TP53, IDH1/2, ERBB, PIK3CA, MET, MYC, BRAF, MGMT, CDKN2A and p16 have been identified as contributors to tumorigenesis, with additional alterations including chromosomal aberrations and epigenetic modifications. These molecular insights reveal several potential therapeutic targets that could address the limited treatment options for GBC. Promising therapeutic avenues under investigation include immune checkpoint inhibitors, tyrosine kinase inhibitors, tumor necrosis factor-related apoptosis-inducing ligands (TRAIL), and phytochemicals. Numerous clinical trials are assessing the efficacy of these targeted therapies. This review provides a detailed examination of GBC's genetic and mutational underpinnings, highlighting critical pathways and emerging therapeutic strategies. We discuss the implications of germline and somatic mutations for early detection and individualized treatment, aiming to bridge current knowledge gaps. By advancing our understanding of GBC's molecular profile, we hope to enhance diagnostic accuracy and improve treatment outcomes, ultimately paving the way for precision medicine approaches in managing GBC.

胆囊癌（GBC）是一种预后较差的侵袭性恶性肿瘤，通常由于早期症状不明显而在晚期被诊断出来。最近的研究提供了GBC的遗传和突变景观的全面视图，揭示了其发病机制中涉及的关键途径。环境暴露，特别是重金属暴露，与GBC风险升高有关。已建立的信号通路，包括激素、凋亡、代谢、炎症和DNA损伤修复通路，是GBC进展的组成部分，有证据表明，特定的种系和体细胞突变参与了其发展。KRAS、TP53、IDH1/2、ERBB、PIK3CA、MET、MYC、BRAF、MGMT、CDKN2A和p16等关键基因突变已被确定为肿瘤发生的因素，此外还有染色体畸变和表观遗传修饰等其他改变。这些分子见解揭示了几个潜在的治疗靶点，可以解决GBC有限的治疗选择。正在研究的有前景的治疗途径包括免疫检查点抑制剂、酪氨酸激酶抑制剂、肿瘤坏死因子相关的凋亡诱导配体（TRAIL）和植物化学物质。许多临床试验正在评估这些靶向治疗的疗效。这篇综述提供了GBC的遗传和突变基础的详细检查，突出了关键途径和新兴的治疗策略。我们讨论了生殖系和体细胞突变对早期检测和个体化治疗的影响，旨在弥合目前的知识差距。通过加深我们对GBC分子特征的理解，我们希望提高诊断的准确性，改善治疗结果，最终为精准医学方法治疗GBC铺平道路。

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引用次数: 0

CUEDC1 promotes the growth, migration, epithelial-mesenchymal transition and inhibits apoptosis of hepatocellular carcinoma cells via the TGF-β/Smad signaling pathway CUEDC1通过TGF-β/Smad信号通路促进肝癌细胞生长、迁移、上皮-间质转化、抑制凋亡

IF 1.9 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis

Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2025.111900

Angjian Zhou , Fuyu Chen , Zhongchao Chen

Purpose

To explore the precise molecular by which CUEDC1, a 42 kDa protein containing a CUE domain located on chromosome 17q22, contributes to liver cancer metastasis.

Method

CUEDC1 protein expression levels were determined in liver cancer cells using Western blot analysis. The expression of CUEDC1 in these cells was silenced through siRNA transfection Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. Cell invasion and migration capabilities were evaluated using Transwell assays. The expression of transforming growth factor-beta (TGF-β)/ small mother against decapentaplegic (Smad) pathway, N-cadherin, alpha -smooth muscle actin (α-SMA), and E-cadherin was detected using Western blot.

Result

CUEDC1 expression was found to be elevated in liver cancer cells. Knockdown of CUEDC1 reduced the expression of TGF-β, p-Smad2, and p-Smad3, key components of the TGF-β/Smad pathway. Additionally, CUEDC1 knockdown significantly decreased cell survival, migration, invasion, and the EMT process in liver cancer cells.

Conclusion

CUEDC1 knockdown markedly reduces EMT and liver cancer cell metastasis by suppressing the TGF-β/Smad signaling pathway.

目的探讨位于染色体17q22上含有CUE结构域的42 kDa蛋白CUEDC1参与肝癌转移的精确分子机制。方法采用Western blot法检测肝癌细胞中cuedc1蛋白的表达水平。通过siRNA转染使CUEDC1在这些细胞中的表达沉默，使用细胞计数试剂盒-8 （CCK-8）测定细胞活力。采用Transwell法评估细胞侵袭和迁移能力。Western blot检测小鼠抗十肢瘫痪（Smad）通路转化生长因子-β (TGF-β)/小母细胞、N-cadherin、α-平滑肌肌动蛋白（α-SMA）、E-cadherin的表达。结果cuedc1在肝癌细胞中表达升高。CUEDC1的下调降低了TGF-β、p-Smad2和p-Smad3的表达，这是TGF-β/Smad通路的关键成分。此外，CUEDC1敲低显著降低肝癌细胞的存活、迁移、侵袭和EMT过程。结论cuedc1基因下调通过抑制TGF-β/Smad信号通路，显著降低EMT和肝癌细胞转移。

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引用次数: 0

E2F1 activates USP19 to affect the stability of c-Myc to facilitate the progression of hepatocellular carcinoma E2F1激活USP19影响c-Myc的稳定性，促进肝细胞癌的进展

IF 1.9 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis

Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2025.111902

Di Zhang, Xinwu Zhang, Shuai Chang, Yao Zhao, Li Zhang

Background

Hepatocellular carcinoma (HCC) is the most common malignant tumor worldwide with a high mortality rate. Herein, this study aims to explore the molecular mechanisms of E2F transcription factor 1 (E2F1), ubiquitin specific peptidase 19 (USP19) and c-Myc in regulating HCC progression.

Methods

RT-qPCR and western blotting were utilized to assess mRNA and protein expression, respectively. The behavior of cells was examined through Methylthiazolyldiphenyl-tetrazolium bromide (MTT), flow cytometry, transwell, and cell sphere formation assays. Glycolysis-related indicators were detected by kits. The interaction between USP19 and c-Myc was measured by co-immunoprecipitation (Co-IP). Dual-luciferase reporter assay and Chromatin Immunoprecipitation (ChIP) assays were used to assess the binding of E2F1 and USP19 promoter. A mouse xenograft model was established for the purpose of analysis in vivo.

Results

High level of c-Myc was observed in HCC tissues and cells. Silencing c-Myc results in the suppression of cell migration, invasion, proliferation, and glycolysis or promotion of apoptosis. USP19 directly bound to c-Myc, and maintained its stability by removing ubiquitination on c-Myc. Overexpression of c-Myc in HCC cells rescued the anti-tumor effect of USP19 deletion. E2F1 promoted USP19 transcription, and increased USP19 expression counteracts the effects of E2F1 depletion on cell behaviors. In vivo, USP19 knockdown controlled HCC growth by modulating c-Myc.

Conclusion

E2F1 activated USP19 transcription, thereby stabilizing c-Myc via deubiquitination and accelerating HCC progression.

背景肝细胞癌（HCC）是世界范围内最常见的恶性肿瘤，死亡率高。本研究旨在探讨E2F转录因子1 （E2F1）、泛素特异性肽酶19 （USP19）和c-Myc调控HCC进展的分子机制。方法采用srt - qpcr和western blotting分别检测mRNA和蛋白的表达。通过甲基噻唑基二苯基四唑溴化铵（MTT）、流式细胞术、transwell和细胞球形成实验来检测细胞的行为。采用试剂盒检测糖酵解相关指标。USP19与c-Myc的相互作用通过共免疫沉淀（Co-IP）测定。采用双荧光素酶报告试验和染色质免疫沉淀（ChIP）试验评估E2F1与USP19启动子的结合。建立小鼠异种移植物模型，进行体内分析。结果肝癌组织和细胞中可见高水平的c-Myc。沉默c-Myc可抑制细胞迁移、侵袭、增殖、糖酵解或促进细胞凋亡。USP19直接与c-Myc结合，并通过去除c-Myc上的泛素化来维持其稳定性。HCC细胞中c-Myc的过表达恢复了USP19缺失的抗肿瘤作用。E2F1促进了USP19的转录，USP19表达的增加抵消了E2F1缺失对细胞行为的影响。在体内，USP19敲低通过调节c-Myc来控制HCC的生长。结论e2f1激活USP19转录，通过去泛素化稳定c-Myc，加速HCC进展。

{"title":"E2F1 activates USP19 to affect the stability of c-Myc to facilitate the progression of hepatocellular carcinoma","authors":"Di Zhang, Xinwu Zhang, Shuai Chang, Yao Zhao, Li Zhang","doi":"10.1016/j.mrfmmm.2025.111902","DOIUrl":"10.1016/j.mrfmmm.2025.111902","url":null,"abstract":"<div><h3>Background</h3><div><span>Hepatocellular carcinoma (HCC) is the most common malignant tumor worldwide with a high mortality rate. Herein, this study aims to explore the molecular mechanisms of </span>E2F transcription factor 1<span> (E2F1), ubiquitin specific peptidase 19 (USP19) and c-Myc in regulating HCC progression.</span></div></div><div><h3>Methods</h3><div><span>RT-qPCR and western blotting<span> were utilized to assess mRNA and protein expression<span>, respectively. The behavior of cells was examined through Methylthiazolyldiphenyl-tetrazolium bromide (MTT), flow cytometry, transwell, and cell sphere formation assays. Glycolysis-related indicators were detected by kits. The interaction between USP19 and c-Myc was measured by co-immunoprecipitation (Co-IP). Dual-luciferase reporter assay and Chromatin Immunoprecipitation (ChIP) assays were used to assess the binding of E2F1 and USP19 promoter. A mouse xenograft model was established for the purpose of analysis </span></span></span><em>in vivo</em>.</div></div><div><h3>Results</h3><div><span>High level of c-Myc was observed in HCC tissues and cells. Silencing c-Myc results in the suppression of cell migration, invasion, proliferation, and glycolysis or promotion of apoptosis. USP19 directly bound to c-Myc, and maintained its stability by removing ubiquitination<span> on c-Myc. Overexpression of c-Myc in HCC cells rescued the anti-tumor effect of USP19 deletion. E2F1 promoted USP19 transcription, and increased USP19 expression counteracts the effects of E2F1 depletion on cell behaviors. </span></span><em>In vivo</em>, USP19 knockdown controlled HCC growth by modulating c-Myc.</div></div><div><h3>Conclusion</h3><div>E2F1 activated USP19 transcription, thereby stabilizing c-Myc via deubiquitination and accelerating HCC progression.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111902"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512011","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}

引用次数: 0

In silico identification of multidrug resistance gene (MDR)-targeted transposon miRNAs in human cancer 人类肿瘤中多药耐药基因（MDR）靶向转座子mirna的计算机鉴定

IF 1.9 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis

Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2025.111903

Seda Mesci̇

miRNAs are small RNA molecules that regulate gene expression and play important roles in various biological processes in cells. The discovery of miRNAs is also of great importance in cancer research. miRNAs enable the development of new approaches in cancer treatment by regulating gene expression in cancer cells and have an important place in cancer development, treatment, and diagnosis. Multidrug resistance (MDR) in cancer is associated with the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. MDR contributes to the dysregulation of ABC transporter proteins, and miRNAs mediate MDR in various cancers, resulting in drug resistance. In this study, it was aimed to identify new miRNA sequences in genes associated with multidrug resistance in cancer using in silico method. After obtaining the mature human miRNA sequences in the miRBASE database, BLAST analyses were performed with these sequences for five multidrug resistance genes (ABCB1, ABCC3, ABCC10, ABCC11, ABCG2) known to be associated with cancer. The RNAhybrid tool was used to find the minimum free energy hybridization of gene and miRNA. The target genes of pre-miRNAs and the metabolic pathways in which the target genes play a role were identified with GeneMANIA, SRplot, miRTargetLink programs. Phylogenetic trees of miRNAs belonging to genes were created using the MEGA X software. Secondary structures of pre-miRNA sequences were determined using the RNAfold Web Server program. According to the data obtained from the study, 107 miRNAs associated with multidrug resistance were identified in human cancers. Transmembrane transporter, drug transport and response to drug functions, and metabolic activities of miRNA-related pathways of MDR genes in various cancer types were determined. Multidrug resistance (MDR) in cancer is often associated with overexpression of ABC transporter proteins, which can lead to failure of cancer treatments. Additionally, the relationship of miRNAs with ABC transporter proteins constitutes an important research area to understand the mechanisms of drug resistance and develop new treatment strategies.

mirna是调节基因表达的小RNA分子，在细胞的各种生物过程中发挥重要作用。mirna的发现在癌症研究中也具有重要意义。mirna通过调节癌细胞中的基因表达，为癌症治疗开辟了新途径，在癌症的发展、治疗和诊断中发挥着重要作用。癌症的多药耐药（MDR）与癌细胞中atp结合盒（ABC）转运蛋白的过度表达有关。MDR导致ABC转运蛋白失调，mirna介导多种癌症的MDR，导致耐药。在本研究中，旨在利用计算机技术鉴定癌症多药耐药相关基因中的新miRNA序列。在miRBASE数据库中获取成熟的人类miRNA序列后，利用这些序列对已知与癌症相关的5个多药耐药基因（ABCB1、ABCC3、ABCC10、ABCC11、ABCG2）进行BLAST分析。使用RNAhybrid工具寻找基因与miRNA的最小自由能杂交。通过GeneMANIA、SRplot、miRTargetLink等程序鉴定pre-miRNAs的靶基因及其代谢途径。使用MEGA X软件建立了属于基因的mirna的系统发育树。使用RNAfold Web Server程序确定pre-miRNA序列的二级结构。根据这项研究获得的数据，在人类癌症中发现了107种与多药耐药相关的mirna。测定不同类型肿瘤中MDR基因的跨膜转运、药物转运及对药物功能的反应、mirna相关通路的代谢活性。癌症中的多药耐药（MDR）通常与ABC转运蛋白的过度表达有关，这可能导致癌症治疗的失败。此外，mirna与ABC转运蛋白的关系是了解耐药机制和制定新的治疗策略的重要研究领域。

{"title":"In silico identification of multidrug resistance gene (MDR)-targeted transposon miRNAs in human cancer","authors":"Seda Mesci̇","doi":"10.1016/j.mrfmmm.2025.111903","DOIUrl":"10.1016/j.mrfmmm.2025.111903","url":null,"abstract":"<div><div><span><span><span>miRNAs are small </span>RNA<span> molecules that regulate gene expression and play important roles in various biological processes<span> in cells. The discovery of miRNAs is also of great importance in cancer research. miRNAs enable the development of new approaches in cancer treatment by regulating gene expression in cancer cells and have an important place in cancer development, treatment, and diagnosis. </span></span></span>Multidrug resistance (MDR) in cancer is associated with the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. MDR contributes to the dysregulation of ABC transporter proteins, and miRNAs mediate MDR in various cancers, resulting in drug resistance. In this study, it was aimed to identify new miRNA sequences in genes associated with multidrug resistance in cancer using </span><em>in silico</em><span><span><span> method. After obtaining the mature human miRNA sequences in the miRBASE database, BLAST analyses were performed with these sequences for five multidrug resistance genes (ABCB1, ABCC3, ABCC10, ABCC11, ABCG2) known to be associated with cancer. The RNAhybrid tool was used to find the minimum free energy hybridization of gene and miRNA. The target genes of pre-miRNAs and the metabolic pathways in which the target genes play a role were identified with GeneMANIA, SRplot, miRTargetLink programs. </span>Phylogenetic trees of miRNAs belonging to genes were created using the MEGA X software. </span>Secondary structures<span><span> of pre-miRNA sequences were determined using the RNAfold Web Server program. According to the data obtained from the study, 107 miRNAs<span> associated with multidrug resistance were identified in human cancers. Transmembrane transporter, drug transport and response to drug functions, and metabolic activities of miRNA-related pathways of MDR genes in various cancer types were determined. </span></span>Multidrug resistance (MDR) in cancer is often associated with overexpression of ABC transporter proteins, which can lead to failure of cancer treatments. Additionally, the relationship of miRNAs with ABC transporter proteins constitutes an important research area to understand the mechanisms of drug resistance and develop new treatment strategies.</span></span></div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111903"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591512","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}

引用次数: 0

The mutagenic properties of formaldehyde and acetaldehyde: Reflections on half a century of progress 甲醛和乙醛的诱变特性：对半个世纪进展的思考。

IF 1.9 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis

Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2024.111886

Mahanish Jung Thapa, Kin Chan

Formaldehyde and acetaldehyde are reactive, small compounds that humans are exposed to routinely, variously from endogenous and exogenous sources. Both small aldehydes are classified as human carcinogens. Investigation of the DNA damaging properties of these two compounds began some 50 years ago. In this review, we summarize progress in this field since its inception over half a century ago, distilling insights gained by the collective efforts of many research groups while highlighting areas for future directions. Over the decades, general consensus about aspects of the mutagenicity of formaldehyde and acetaldehyde has been reached. But other characteristics of formaldehyde and acetaldehyde remain incompletely understood and require additional investigation. These include crucial details about the mutational signature(s) induced and possible mechanistic role(s) during carcinogenesis.

甲醛和乙醛是人类经常接触到的反应性小化合物，其来源有内源性和外源性之分。这两种小醛类物质都被列为人类致癌物。对这两种化合物 DNA 损伤特性的研究始于大约 50 年前。在这篇综述中，我们总结了这一领域自半个多世纪前开始研究以来所取得的进展，提炼了许多研究小组共同努力所获得的见解，同时强调了未来的研究方向。几十年来，人们已就甲醛和乙醛的致突变性达成了普遍共识。但是，人们对甲醛和乙醛的其他特性仍不完全了解，需要进行更多的研究。其中包括诱发突变特征的关键细节以及在致癌过程中可能发挥的机理作用。

引用次数: 0

APOC1, transcriptionally regulated by FOXM1, promotes M2 macrophage polarization and cervical cancer progression FOXM1转录调控的APOC1促进M2巨噬细胞极化和宫颈癌进展

IF 1.9 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis

Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2025.111904

Qing Chai, Yan Qi, Xiaoyan Nie, Huan Wang

Background

Cervical cancer (CC) is a common malignant tumor in women. M2 macrophages are associated with tumor growth, metastasis, and immunosuppression. Apolipoprotein C1 (APOC1) has been confirmed as an oncogene in CC. However, the role and mechanism of APOC1 in CC progression and M2 macrophages remain to be elucidated.

Methods

The effects of APOC1 on CC cell malignant phenotypes were examined by CCK-8, colony formation, wound healing, and transwell assays in vitro and mice transplant tumor model in vivo. M2 macrophage polarization was assessed by qRT-PCR and flow cytometry assays. The interaction between APOC1 and forkhead box M1 (FOXM1) was determined using chromatin immunoprecipitation (ChIP) and luciferase reporter assays.

Results

The expression of APOC1 and FOXM1 was upregulated in CC tissues and cells. Knockdown of APOC1 or FOXM1 resulted in the inhibition of cell proliferation, migration, invasion, and EMT. Moreover, the polarization of M2 macrophages was attenuated when APOC1 or FOXM1 was silenced. Mechanistically, FOXM1 transcriptionally activated APOC1 by binding to its promoter. Furthermore, overexpression of APOC1 reversed the inhibitory effects of FOXM1 knockdown on cell proliferation, metastasis, and M2 macrophage polarization. Additionally, the knockdown of APOC1 reduced tumor growth and M2 macrophage polarization in mice.

Conclusion

FOXM1/APOC1 axis is involved in the progression of CC and the regulation of M2 macrophages polarization, bringing new hope to the treatment of CC.

宫颈癌（CC）是女性常见的恶性肿瘤。M2巨噬细胞与肿瘤生长、转移和免疫抑制有关。载脂蛋白C1 （APOC1）已被证实是CC的致癌基因，但APOC1在CC进展和M2巨噬细胞中的作用和机制仍有待阐明。方法采用体外CCK-8、菌落形成、创面愈合、transwell实验及小鼠移植瘤模型检测APOC1对CC细胞恶性表型的影响。采用qRT-PCR和流式细胞术检测M2巨噬细胞极化情况。采用染色质免疫沉淀法（ChIP）和荧光素酶报告基因法测定APOC1与叉头盒M1 （FOXM1）之间的相互作用。结果CC组织和细胞中APOC1和FOXM1表达上调。敲低APOC1或FOXM1导致细胞增殖、迁移、侵袭和EMT受到抑制。此外，当APOC1或FOXM1被沉默时，M2巨噬细胞的极化减弱。机制上，FOXM1通过结合其启动子转录激活了APOC1。此外，APOC1的过表达逆转了FOXM1敲低对细胞增殖、转移和M2巨噬细胞极化的抑制作用。此外，敲低APOC1可降低小鼠肿瘤生长和M2巨噬细胞极化。结论foxm1 /APOC1轴参与了CC的发展和M2巨噬细胞极化的调控，为CC的治疗带来了新的希望。

{"title":"APOC1, transcriptionally regulated by FOXM1, promotes M2 macrophage polarization and cervical cancer progression","authors":"Qing Chai, Yan Qi, Xiaoyan Nie, Huan Wang","doi":"10.1016/j.mrfmmm.2025.111904","DOIUrl":"10.1016/j.mrfmmm.2025.111904","url":null,"abstract":"<div><h3>Background</h3><div><span>Cervical cancer (CC) is a common malignant tumor in women. </span>M2 macrophages<span><span> are associated with tumor growth, metastasis, and immunosuppression. </span>Apolipoprotein<span> C1 (APOC1) has been confirmed as an oncogene in CC. However, the role and mechanism of APOC1 in CC progression and M2 macrophages remain to be elucidated.</span></span></div></div><div><h3>Methods</h3><div><span>The effects of APOC1 on CC cell malignant phenotypes were examined by CCK-8, colony formation, wound healing, and transwell assays </span><em>in vitro</em><span> and mice transplant tumor model </span><em>in vivo</em><span>. M2 macrophage polarization was assessed by qRT-PCR and flow cytometry assays. The interaction between APOC1 and forkhead box M1 (FOXM1) was determined using chromatin immunoprecipitation<span> (ChIP) and luciferase reporter assays.</span></span></div></div><div><h3>Results</h3><div>The expression of APOC1 and FOXM1 was upregulated in CC tissues and cells. Knockdown of APOC1 or FOXM1 resulted in the inhibition of cell proliferation<span>, migration, invasion, and EMT<span>. Moreover, the polarization of M2 macrophages was attenuated when APOC1 or FOXM1 was silenced. Mechanistically, FOXM1 transcriptionally activated APOC1 by binding to its promoter. Furthermore, overexpression of APOC1 reversed the inhibitory effects of FOXM1 knockdown on cell proliferation, metastasis, and M2 macrophage polarization. Additionally, the knockdown of APOC1 reduced tumor growth and M2 macrophage polarization in mice.</span></span></div></div><div><h3>Conclusion</h3><div>FOXM1/APOC1 axis is involved in the progression of CC and the regulation of M2 macrophages polarization, bringing new hope to the treatment of CC.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111904"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696726","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}

引用次数: 0

Cytotoxicity of allyl isothiocyanate and its metabolites in hepatocellular carcinoma HepG2 cells 异硫氰酸烯丙酯及其代谢物对肝癌HepG2细胞的细胞毒性

IF 1.9 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis

Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2025.111899

Takashi Hashimoto , Shino Nakamura , Takeshi Suzuki , Yuka Hasegawa , Kazuki Kanazawa

Objective

To investigate the mechanisms by which allyl isothiocyanate (AITC) exerts its anticancer effects, the present study investigated the cytotoxic effects of AITC and its metabolites on hepatocellular carcinoma HepG2 cells.

Methods

The AITC metabolites, S-(N-allylthiocarbamoyl)-L-glutathione (AITC-GSH), N-acetyl-S-(N-allylthiocarbamoyl)-L-cysteine (NAC-AITC), S-(N-allylthiocarbamoyl)-L-cysteinylglycine (AITC-Cys-Gly), and S-(N-allylthiocarbamoyl)-L-cysteine (AITC-Cys) were synthesized. HepG2 cells were treated with these compounds and AITC and subjected to a cell cycle analysis, HPLC analysis for intracellular AITC metabolites, and intracellular reactive oxygen species (ROS) analysis.

Results

AITC, AITC-GSH, and NAC-AITC significantly induced cell cycle arrest in the G₂/M phase and subsequently enhanced apoptotic cell death. The AITC metabolites, AITC-Cys-Gly and AITC-Cys did not induce cell cycle arrest. A correlation was observed between the intracellular concentration of AITC-GSH and the percentage of cells under G₂/M arrest after the treatments with AITC, AITC-GSH, and NAC-AITC. AITC derived from HepG2 cells treated with AITC-GSH and NAC-AITC conjugated with endogenous GSH, resulting in an increase in ROS levels. A treatment with a ROS inhibitor canceled cell cycle arrest.

Conclusion

The conjugation of intracellular GSH with AITC decreased free reduced GSH levels and increased intracellular ROS levels in HepG2 cells, resulting in cytotoxicity, including cell cycle arrest and apoptosis.

目的探讨异硫氰酸烯丙酯（allyl isothiocyanate， AITC）的抗肿瘤作用机制，研究AITC及其代谢物对肝癌HepG2细胞的细胞毒作用。方法合成AITC代谢产物S-（n -烯丙基硫代氨基甲酸酯）- l-谷胱甘肽（AITC- gsh）、n -乙酰基-S-（n -烯丙基硫代氨基甲酸酯）- l-半胱氨酸（NAC-AITC）、S-（n -烯丙基硫代氨基甲酸酯）- l-半胱氨酸（AITC- cys - gly）、S-（n -烯丙基硫代氨基甲酸酯）- l-半胱氨酸（AITC- cys - gly）和S-（n -烯丙基硫代氨基甲酸酯）- l-半胱氨酸（AITC- cys - gly）。用这些化合物和AITC处理HepG2细胞，并进行细胞周期分析、细胞内AITC代谢物的HPLC分析和细胞内活性氧（ROS）分析。结果saitc、AITC-GSH和NAC-AITC显著诱导细胞周期阻滞在G2/M期，随后增强凋亡细胞死亡。AITC代谢物、AITC- cys - gly和AITC- cys不诱导细胞周期阻滞。AITC、AITC- gsh和NAC-AITC处理后，细胞内AITC- gsh浓度与G2/M阻滞细胞百分比呈正相关。AITC来源于HepG2细胞，经AITC-GSH和NAC-AITC结合内源性GSH处理，导致ROS水平升高。用ROS抑制剂治疗可以消除细胞周期阻滞。结论AITC与细胞内GSH结合可降低HepG2细胞游离还原GSH水平，增加细胞内ROS水平，引起细胞毒性，包括细胞周期阻滞和细胞凋亡。

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引用次数: 0

Integrating classical genetics and whole-genome sequencing to reveal the chromosomal basis of hygromycin resistance in Escherichia coli 整合经典遗传学和全基因组测序揭示大肠杆菌耐潮霉素的染色体基础

IF 1.9 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis

Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2025.111906

Madhumathi Irulappan , Prabhakara Sethupathy Ramkumar , Jeyaprakash Rajendhran , M. Hussain Munavar , Singaravelan Balasubramaniam

Hygromycin B (HygB), a broad-spectrum antibiotic, is widely used in molecular biology, agriculture, and veterinary medicine. It inhibits protein synthesis by binding to ribosomes, and its plasmid-borne resistance gene serves as a selectable marker for applications in gene manipulation technologies. The binding site of the P1 phage-borne toxin Doc, which induces bacterial apoptosis, overlaps with the binding site of HygB in helix h44 of 16S rRNA. Hence isolation and characterization of chromosomal HygB resistance would largely serve as gateway to understand the less studied but imperative and emerging modes of drug resistance like bacterial multicellularity and heteroresistance. In this study we have investigated the chromosomal origin of HygB resistance in E. coli through a combination of classical genetics and whole-genome sequencing. Eight HygB-resistant mutants were analyzed, and co-transduction experiments revealed a narrow region (71.8–75.8 min) to have conferred resistance. Whole-genome sequencing confirmed a single base pair change in the fusA gene (A1754 to G1754) as the cause. This is a maiden report on a missense mutation of fusA leading to HygB resistance and these findings provide valuable insights into the mechanisms of HygB resistance.

潮霉素B （HygB）是一种广谱抗生素，广泛应用于分子生物学、农业、兽医学等领域。它通过与核糖体结合抑制蛋白质合成，其质粒携带的抗性基因可作为基因操作技术应用的选择性标记。诱导细菌凋亡的P1噬菌体毒素Doc的结合位点与16S rRNA螺旋h44中HygB的结合位点重叠。因此，染色体HygB耐药的分离和鉴定将在很大程度上为了解细菌多细胞耐药和异源耐药等研究较少但势在必行的耐药模式提供途径。在这项研究中，我们通过经典遗传学和全基因组测序的结合研究了大肠杆菌HygB抗性的染色体起源。对8个hygb耐药突变体进行了分析，共转导实验显示一个狭窄的区域（71.8-75.8 min）产生了抗性。全基因组测序证实了fusA基因（A1754到G1754）的单个碱基对变化是原因。这是关于fusA错义突变导致HygB耐药的首次报道，这些发现为HygB耐药机制提供了有价值的见解。

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