Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis最新文献

{"title":"Platinum-based targeted chemotherapies and reversal of cisplatin resistance in non-small cell lung cancer (NSCLC)","authors":"Hassaan Umar ,&nbsp;Habibah A. Wahab ,&nbsp;Ali Attiq ,&nbsp;Muhammad Wahab Amjad ,&nbsp;Syed Nasir Abbas Bukhari ,&nbsp;Waqas Ahmad","doi":"10.1016/j.mrfmmm.2024.111856","DOIUrl":"https://doi.org/10.1016/j.mrfmmm.2024.111856","url":null,"abstract":"<div><p>Lung cancer is the one of the most prevalent cancer in the world. It kills more people from cancer than any other cause and is especially common in underdeveloped nations. With 1.2 million instances, it is also the most prevalent cancer in men worldwide, making about 16.7% of the total cancer burden. Surgery is the main form of curative treatment for early-stage lung cancer. However, the majority of patients had incurable advanced non-small cell lung cancer (NSCLC) recurrence after curative purpose surgery, which is indicative of the aggressiveness of the illness and the dismal outlook. The gold standard of treatment for NSCLC patients includes drug targeting of specific mutated genes drive in development of lung cancer. Furthermore, patients with advanced NSCLC and those with early-stage illness needing adjuvant therapy should use cisplatin as it is the more active platinum drug. So, this review encompasses the non-small cell lung cancer microenvironment, treatment approaches, and use of cisplatin as a first-line regimen for NSCLC, its mechanism of action, cisplatin resistance in NSCLC and also the prevention strategies to revert the drug resistance.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"828 ","pages":"Article 111856"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140187452","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":"Low-molecular-weight fucoidan increases telomere length and immunostimulatory effects on NK-92 cells following inhaled anesthetic injury","authors":"Cheng-Hsi Chang ,&nbsp;Pai-An Hwang","doi":"10.1016/j.mrfmmm.2024.111857","DOIUrl":"https://doi.org/10.1016/j.mrfmmm.2024.111857","url":null,"abstract":"<div><p>Inhaled anesthetics, such as isoflurane, may cause side effects, including short-term immunosuppression and DNA damage. In contrast, low molecular weight fucoidan (LMF), derived from brown seaweed, exhibits promising immunomodulatory effects. In this study, we determined the effect of isoflurane on telomeres and examined the potential of LMF to ameliorate the harmful effects of isoflurane. Male Lewis rats, the mouse lymphoma cell line YAC-1, and the human nature killer cell line NK-92 MI were exposed to isoflurane. The relative telomere length (T/S) ratio and mRNA expression were determined by quantitative PCR. The viability assay was used to assess cell viability. In vivo, 2% isoflurane exposure, which is a clinically relevant concentration, reduced telomere length, and correlated with exposure frequency and duration. Isoflurane concentrations above 2% shortened YAC-1 telomeres, with minimal impact on cell viability. LMF pre-treatment enhanced NK-92 MI cell survival resulting from isoflurane exposure and exerted superior telomere protection compared with LMF post-treatment. Furthermore, adding LMF during isoflurane exposure resulted in a significant increase in IFN-γ, TNF-α, and IL-10 mRNA compared with the untreated group. LMF protected against isoflurane-induced telomere shortening, enhanced NK cell viability, and modulated cytokine expression, thus mitigating postoperative immune suppression and risk of tumor metastasis.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"828 ","pages":"Article 111857"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140543720","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":"High expression of TRIP13 is associated with tumor progression in H. pylori infection induced gastric cancer","authors":"Longxiang Wu ,&nbsp;Qiu Xue ,&nbsp;Xiaochun Xia","doi":"10.1016/j.mrfmmm.2024.111854","DOIUrl":"https://doi.org/10.1016/j.mrfmmm.2024.111854","url":null,"abstract":"<div><h3>Background/objective</h3><p><em>H. pylori</em> is a recognized bacterial carcinogen in the world to cause gastric cancer (GC). However, the molecular mechanism of <em>H. pylori</em> infection-induced GC is not completely clear. Thus, there is an urgent need to reveal the precise mechanisms regulating cancer development due to <em>H. pylori</em> infection.</p></div><div><h3>Methods</h3><p>GEO microarray databases and TCGA databases were extracted for the analysis of different expression genes (DEGs). Then, Kaplan-Meier Plotter was used for prognostic analysis. Functional enrichment analysis of TRIP13 was performed by metascape database and TIMER database. Specific role of TRIP13 in GC with <em>H. pylori</em> infection was confirmed by CCK8, cell cycle analysis and WB.</p></div><div><h3>Results</h3><p>A total 10 DEGs were substantially elevated in GC and <em>H. pylori</em>+ tissues and might be associated with <em>H. pylori</em> infection in GC and only the highly expressed TRIP13 was statistically associated with poor prognosis in GC patients. Meanwhile, TRIP13 were upregulated in both CagA-transfected epithelial cells and GC cells. And TRIP13 deficiency inhibited cell proliferation and arrested the cell cycle at the G1 phase.</p></div><div><h3>Conclusion</h3><p>Our study suggested that high expression of TRIP13 can promote the proliferation, cell cycle in GC cells, which could be used as a biomarker for <em>H. pylori</em> infection GC.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"828 ","pages":"Article 111854"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140134917","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":"Mechanisms of piperonyl butoxide cytotoxicity and its enhancement with imidacloprid and metals in Chinese hamster ovary cells","authors":"Mai M. Awad ,&nbsp;Piyawan Chailapakul ,&nbsp;Mark.A. Brown ,&nbsp;Takamitsu A. Kato","doi":"10.1016/j.mrfmmm.2024.111853","DOIUrl":"10.1016/j.mrfmmm.2024.111853","url":null,"abstract":"<div><p>The widespread use of chemicals and the presence of chemical and metal residues in various foods, beverages, and other consumables have raised concerns about the potential for enhanced toxicity. This study assessed the cytotoxic effects of Piperonyl butoxide (PBO) and its enhancement by combination with major contamination chemicals including Imidacloprid and metals, using different cytotoxic and genotoxic assays in Chinese hamster ovary (CHO) cells. PBO exhibited elevated cytotoxic effects in poly (ADP-ribose) polymerase (PARP) deficient CHO mutants but not in Glutathione S-transferase deficient CHO mutants. PBO cytotoxicity was enhanced by PARP inhibitor, Olaparib. PBO cytotoxicity was also enhanced with co-exposure to Imidacloprid, Lead Chloride, or Sodium Selenite. PBO induces <strong>γ</strong>H2AX foci formation and apoptosis. The induction of DNA damage markers was elevated with PARP deficiency and co-exposure to Imidacloprid, Lead Chloride, or Sodium Selenite. Moreover, PBO triggers to form etch pits on plastic surfaces. These results revealed novel mechanisms of PBO cytotoxicity associated with PARP and synergistic effects with other environmental pollutants. The toxicological mechanisms underlying exposure to various combinations at different concentrations, including concentrations below the permitted limit of intake or the level of concern, require further study.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"828 ","pages":"Article 111853"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139896848","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":"Allium cepa tests: Exploring bleomycin induced cyto-genotoxicity and altered cell cycle kinetics in root tips meristematic cells","authors":"Ria Das,&nbsp;Sanjib Ray","doi":"10.1016/j.mrfmmm.2024.111851","DOIUrl":"10.1016/j.mrfmmm.2024.111851","url":null,"abstract":"<div><p>Bleomycin, commonly employed in treating Hodgkin’s lymphoma and testicular cancer, is associated with significant pulmonary toxicity. While various studies have assessed the toxic impact of chemotherapeutic agents on aquatic and terrestrial environments, limited data exist on bleomycin's effects, especially concerning higher plants. To address this gap, we utilized the <em>Allium cepa</em> assays, renowned for evaluating chemical and biochemical agents' toxic effects, to investigate bleomycin's impact on the terrestrial ecosystem. Our study aimed to assess bleomycin's cyto-genotoxic effects on <em>A. cepa</em> root tip cells at minimal concentrations (10–40 μg mL⁻¹) and varied exposure durations (2, 4, 6, and 24 h). Analysis of nuclear and mitotic abnormalities in bleomycin-treated <em>A. cepa</em> root tip cells, alongside an acridine orange-ethidium bromide double staining assay, illuminated its influence on cell viability. Additionally, agarose gel electrophoresis determined the drug's potential for DNA degradation, unveiling the underlying mechanisms of cyto-genotoxicity. Results also demonstrated a decline in the mitotic index with increased bleomycin concentrations and exposure time, elevated frequencies of various cyto-genotoxic abnormalities, including sticky chromosomes, chromatid breaks, laggards, bridges, polar deviations, nuclear lesions, and hyperchromasia. The study indicated the potential risks of bleomycin even at low concentrations and brief exposures, highlighting its severe adverse effects on genetic material of plant, potentially contributing to cell death. Consequently, this investigation unveils bleomycin's cyto-genotoxic effects on higher plant system, underscoring its threat to terrestrial ecosystems, particularly upon chronic and unmonitored exposure.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"828 ","pages":"Article 111851"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139893946","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":"LINC00665 target let-7i/HMGA1 promotes the proliferation and invasion of hepatoma cells","authors":"Bo-chao Zhang ,&nbsp;Si-yuan Ma ,&nbsp;Ping Zhu ,&nbsp;Liang-yu Zhu ,&nbsp;Xiao-xiao Zhao ,&nbsp;Chun Pu","doi":"10.1016/j.mrfmmm.2024.111852","DOIUrl":"10.1016/j.mrfmmm.2024.111852","url":null,"abstract":"<div><h3>Objectives</h3><p>Our group previously found that LINC00665 was upregulated in hepatocellular carcinoma (HCC) tissues through database analysis; however, the potential molecular mechanism of LINC00665 in HCC progression still needs further study.</p></div><div><h3>Methods</h3><p>qRT<img>PCR was performed to determine the differential expression of LINC00665 and let-7i in HCC cells. Dual-luciferase reporter assays were performed to analyze the interaction of LINC00665 and let-7i. CCK-8 assays, scratch assays, Transwell invasion assays, qRT<img>PCR and western blotting were performed to determine the regulatory mechanism of LINC00665/let-7i/HMGA1 in HCC cells.</p></div><div><h3>Results</h3><p>LINC00665 was upregulated in HCC cells compared with normal hepatocytes. A potential binding site between LINC00665 and let-7i was confirmed by dual-luciferase reporter assay. In HCC cells, inhibition of LINC00665 significantly reduced cell proliferation, migration and invasion ability via the let-7i/HMGA1 signaling axis.</p></div><div><h3>Conclusion</h3><p>LINC00665 promotes the proliferation and invasion of HCC cells via the let-7i/HMGA1 signaling axis.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"828 ","pages":"Article 111852"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0027510724000022/pdfft?md5=8d9fc88d5d09a9dc4462548b36a1802d&pid=1-s2.0-S0027510724000022-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139897099","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":"A positive correlation between mutated gene of sickle cell anemia and glucose-6-phosphate dehydrogenase among gond tribes of Chhattisgarh, India","authors":"Ekta Singh,&nbsp;Lohit Raj Shivwanshi,&nbsp;Anil Kumar","doi":"10.1016/j.mrfmmm.2023.111849","DOIUrl":"https://doi.org/10.1016/j.mrfmmm.2023.111849","url":null,"abstract":"<div><h3>Background</h3><p>Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy<span> affecting millions of individuals worldwide. It is believed that the prevalence of G6PD deficiency in different ethnic populations increases its association with other pathological conditions especially sickle cell anemia (SCA), as they both are well-known adaptations against malaria. Thus, the present study aims to determine the frequency of G6PD deficiency among SCA patients and the association between them in the tribal community (Gond) of Chhattisgarh, India.</span></p></div><div><h3>Method</h3><p><span>A total of 810 samples from three different age groups i.e., 10–20, 21–30, and 31–40 years were collected from the tribal community (Gond) of Kabirdham district of Chhattisgarh. The frequency of SCA was determined by a slide test followed by cellulose acetate<span> paper electrophoresis<span> and G6PD deficiency by methemoglobin reduction test. Glutathione-S-Transferase (GST) </span></span></span>gene polymorphism in sickle celled individuals and variant analysis in G6PD deficient individuals were analyzed by RT-PCR.</p></div><div><h3>Results</h3><p>The frequency of SCA and G6PD deficiency was reported at 9.75% and 17.16% respectively and a high degree of positive correlation between SCA and G6PD deficiency was also found (HbSS-G6PD deficient: r = 0.84, <em>p</em> = .356; HbAS-G6PD deficient: r = 0.89, <em>p</em><span><span> = .345). Results of the GST gene revealed that GSTM1 and GSTT1 genes are present in almost all sickled individuals while </span>GSTP1 and GSTP1a exist in the mutated form in a maximum percentage of individuals. G6PD variant analysis also showed that 70% and 60% of individuals have mutated Mahidol and Union variants respectively, while none of the individuals have mutated Chinese variants.</span></p></div><div><h3>Conclusion</h3><p>A high degree of correlation between SCA and G6PD was reported among Gond tribes of Chhattisgarh, India with a high degree of mutated GSTP1, GSTP1a, Mahidol, and Union variants. The study makes it possible to take specific preventive measures concerning the medication of anti-oxidizing drugs.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"828 ","pages":"Article 111849"},"PeriodicalIF":2.3,"publicationDate":"2023-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138839574","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":"Evaluation of the effects of simulated hypoxia by CoCl2 on radioresistance and change of hypoxia-inducible factors in human glioblastoma U87 tumor cell line","authors":"Elham Khakshour ,&nbsp;Mohammad Taghi Bahreyni-Toossi ,&nbsp;Kazem Anvari ,&nbsp;Mohammad Amin Shahram ,&nbsp;Fereshteh Vaziri-Nezamdoust ,&nbsp;Hosein Azimian","doi":"10.1016/j.mrfmmm.2023.111848","DOIUrl":"https://doi.org/10.1016/j.mrfmmm.2023.111848","url":null,"abstract":"<div><h3>Purpose</h3><p>Glioblastoma<span><span> (GBM) is considered the most common and lethal type of brain tumor with a poor prognosis. GBM treatment has challenges due to its aggressive nature, which often causes treatment failure and recurrence. Hypoxia is one of the characteristics of glioblastoma tumors that contribute to </span>radioresistance<span> and malignant phenotypes of GBM. In this study, we aimed to determine the effects of hypoxia on the radiosensitivity of U87 GBM cells by the hypoxia-mimicking model.</span></span></p></div><div><h3>Methods</h3><p>Following the treatment of cells with different concentrations of CoCl₂<span>, an MTT assay was used to evaluate the cytotoxicity of CoCl</span>₂<span>. To understand the effects of Ionizing radiation on CoCl</span>₂-treated groups, cells were exposed to irradiation after pretreating with 100 μM CoCl_2,<span> and a clonogenic survival assay was performed to determine the radiosensitivity of U87 cells. Also, the intracellular Reactive oxygen level was measured by 2′,7′–dichlorofluorescein diacetate<span> (DCFDA) probe staining. Additionally, the expression of hypoxia-associated genes, including HIF-1α, HIF-2α, and their target genes (GLUT-1), was monitored by reverse transcription polymerase chain reaction (RT-PCR).</span></span></p></div><div><h3>Results</h3><p><span>Our study revealed that the cell viability of CoCl</span>₂-treated cells was decreased in a concentration-dependent manner. Also, CoCl₂ did not cause any cytotoxicity on U87 cells at a concentration of 100 μM after treatment for 24 h. Colony formation assay showed that CoCl₂<span> pretreatment induced radioresistance of tumor cells compared to non-treated cells. Also, CoCl</span>₂ can protect cells against irradiation by the clearance of ROS. Moreover, Real-time results showed that the mRNA expression of HIF-1α and GLUT-1 were significantly upregulated following hypoxia induction and/or irradiation condition. However, the level of HIF-2α mRNA did not change significantly in hypoxia or irradiation alone conditions, but it increased significantly only in hypoxia + irradiation conditions.</p></div><div><h3>Conclusion</h3><p>Taken together, our results indicated that simulating hypoxia by CoCl₂ can effectively increase hypoxia-associated genes, specially HIF-1α and GLUT-1, but did not affect HIF-2α gene expression. Also, it can increase the clearance of ROS, respectively, and it leads to inducing radioresistance of U87 cells.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"828 ","pages":"Article 111848"},"PeriodicalIF":2.3,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139050407","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":"Higher TP53 somatic mutation prevalence from liquid biopsy analysis in ever smoker non-small-cell lung cancer patients","authors":"Haktan Bağış Erdem ,&nbsp;Mustafa Tarık Alay ,&nbsp;Zeynep Özdemir ,&nbsp;Ezgi Çevik ,&nbsp;Öztürk Ateş ,&nbsp;Cengiz Karaçin ,&nbsp;İbrahim Şahin ,&nbsp;Mutlu Doğan ,&nbsp;Taha Bahsi","doi":"10.1016/j.mrfmmm.2023.111847","DOIUrl":"10.1016/j.mrfmmm.2023.111847","url":null,"abstract":"<div><h3>Objective</h3><p>Cigarette smoking is a primary risk factor, linked to 80% of LC deaths. TP53, a key gene, is implicated in various cancers, with TP53 alterations in 36.7% of cancers. This research aims to investigate TP53 mutations detected in NSCLC patients by liquid biopsy and explore the relationship between these mutations and smoking history.</p></div><div><h3>Material and method</h3><p>The study enrolled a total of 340 patients diagnosed with non-small cell lung cancer (NSCLC). For sequencing, the Illumina NextSeq 500 system was utilized. The oncogenicity of the variants was assessed according to the ClinGen/CGC/VICC SOP and the variants were categorized into four tiers according to AMP/ASCO/CAP.</p></div><div><h3>Results</h3><p>The most common mutations were in TP53 (48.7%), followed by EGFR, PIK3CA, and PTEN. Missense mutations<span> were frequent, with TP53 and EGFR having higher rates in ever-smokers. No indels or complex mutations were found in ever-smokers. Patient age ranged from 20 to 86 years. Tier I-II variants were more common in ever-smokers, while Tier III variants were prevalent in never-smokers. TP53 mutations were more frequent in ever-smokers, showing a strong association with smoking. Domain distribution showed differences in PIK3CA. Transversion/transition ratios varied by gene and smoking status.</span></p></div><div><h3>Discussion</h3><p>The presence of TP53 mutations is strongly associated with both cigarette smoking and elevated Tv/Ti ratios. The tier status of TP53, EGFR, and PTEN variants does not show a specific domain distribution, but interesting associations are observed between the tier status and domain distribution in PIK3CA variants. Therefore, further comprehensive investigations are needed to explore this entity, as well as the underlying factors contributing to the increased Tv/Ti rates in the TP53 gene. Such research will provide deeper insights into the genetic alterations associated with smoking and tumor heterogeneity, ultimately aiding in the development of targeted therapies.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"828 ","pages":"Article 111847"},"PeriodicalIF":2.3,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138496271","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":"Variants in exon 2 of MED12 gene causes uterine leiomyoma’s through over-expression of MMP-9 of ECM pathway","authors":"Vivek Pandey ,&nbsp;Priyanka Jain ,&nbsp;Souradip Chatterjee ,&nbsp;Anjali Rani ,&nbsp;Anima Tripathi ,&nbsp;Pawan K. Dubey","doi":"10.1016/j.mrfmmm.2023.111839","DOIUrl":"10.1016/j.mrfmmm.2023.111839","url":null,"abstract":"<div><h3>Aims</h3><p>To study the impact of Mediator complex subunit 12 (MED12) gene variants on the encoded protein’s function and pathogenic relevance for genesis of uterine leiomyoma’s (ULs).</p></div><div><h3>Methods</h3><p>Mutational analysis in exon-2 of MED12 gene was performed by PCR amplification and DNA sequencing<span> in 89 clinically diagnosed ULs tissues. Pathogenicity<span> prediction of variation was performed by computational analysis. The functional effects of missense<span> variation were done by quantity RT-PCR and western blot analysis.</span></span></span></p></div><div><h3>Result(s)</h3><p>Out of 89 samples, 40 (44.94%) had missense variation in 14 different CDS position of exon-2 of MED12 gene. Out of 40 missense variation, codon 44 had 25 (62.5%) looking as a hotspot region for mutation for ULs, because CDS position c130 and c131present at codon 44 that have necleotide change G&gt;A, T, C at c130 and c131 have necleotide change G&gt;A and C. We also find somenovel somatic mutations<span><span> oncodon 36 (T &gt; C), 38 (G&gt;T) of exon-2 and 88 (G&gt;C) of intron-2. No mutations were detected in uterine myometrium samples. Our computational analysis suggests that change in Med12c .131 G&gt;A leads to single substitution of amino acid [Glycine (G) to </span>Aspartate<span> (D)] which has a pathogenic and lethal impact and may cause instability of MED12 protein. Further, analysis of extracellular matrix (ECM) component (MMP-2 &amp; 9, COL4A2 and α-SMA) mRNA and protein expression levels in the set of ULs having MED12 mutation showed significantly higher expression of MMP-9 and α-SMA.</span></span></p></div><div><h3>Conclusion(s)</h3><p>The findings of present study suggest that missense variation in codon 44 of MED12 gene lead to the genesis of leiomyoma’s through over-expression of MMP-9 of ECM pathway which could be therapeutically targeted for non-surgical management of ULs.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"828 ","pages":"Article 111839"},"PeriodicalIF":2.3,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135665048","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}