Pub Date : 2025-01-01Epub Date: 2025-02-11DOI: 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.
{"title":"CUEDC1 promotes the growth, migration, epithelial-mesenchymal transition and inhibits apoptosis of hepatocellular carcinoma cells via the TGF-β/Smad signaling pathway","authors":"Angjian Zhou , Fuyu Chen , Zhongchao Chen","doi":"10.1016/j.mrfmmm.2025.111900","DOIUrl":"10.1016/j.mrfmmm.2025.111900","url":null,"abstract":"<div><h3>Purpose</h3><div>To explore the precise molecular by which CUEDC1<span>, a 42 kDa protein containing a CUE domain located on chromosome 17q22, contributes to liver cancer metastasis.</span></div></div><div><h3>Method</h3><div><span><span><span>CUEDC1 </span>protein expression levels were determined in liver </span>cancer cells using </span>Western blot analysis<span><span><span>. The expression of CUEDC1 in these cells was silenced through </span>siRNA transfection </span>Cell viability<span> 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.</span></span></div></div><div><h3>Result</h3><div>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.</div></div><div><h3>Conclusion</h3><div><span>CUEDC1 knockdown markedly reduces EMT and liver cancer cell metastasis by suppressing the TGF-β/Smad </span>signaling pathway.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111900"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394418","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}
Pub Date : 2025-01-01Epub Date: 2024-11-08DOI: 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。
{"title":"The mutagenic properties of formaldehyde and acetaldehyde: Reflections on half a century of progress","authors":"Mahanish Jung Thapa, Kin Chan","doi":"10.1016/j.mrfmmm.2024.111886","DOIUrl":"10.1016/j.mrfmmm.2024.111886","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111886"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645346","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}
Pub Date : 2025-01-01Epub Date: 2025-03-20DOI: 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.
{"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}
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.
{"title":"Integrating classical genetics and whole-genome sequencing to reveal the chromosomal basis of hygromycin resistance in Escherichia coli","authors":"Madhumathi Irulappan , Prabhakara Sethupathy Ramkumar , Jeyaprakash Rajendhran , M. Hussain Munavar , Singaravelan Balasubramaniam","doi":"10.1016/j.mrfmmm.2025.111906","DOIUrl":"10.1016/j.mrfmmm.2025.111906","url":null,"abstract":"<div><div><span><span><span>Hygromycin B (HygB), a broad-spectrum antibiotic, is widely used in </span>molecular biology<span>, agriculture, and veterinary medicine. It inhibits protein synthesis<span> by binding to ribosomes, and its plasmid-borne resistance gene serves as a selectable marker<span> 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 </span></span></span></span>16S rRNA<span>. 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 </span></span><em>E. coli</em><span> 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 </span><em>fusA</em><span> gene (A1754 to G1754) as the cause. This is a maiden report on a missense mutation of </span><em>fusA</em> leading to HygB resistance and these findings provide valuable insights into the mechanisms of HygB resistance.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111906"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928803","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}
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.
{"title":"Cytotoxicity of allyl isothiocyanate and its metabolites in hepatocellular carcinoma HepG2 cells","authors":"Takashi Hashimoto , Shino Nakamura , Takeshi Suzuki , Yuka Hasegawa , Kazuki Kanazawa","doi":"10.1016/j.mrfmmm.2025.111899","DOIUrl":"10.1016/j.mrfmmm.2025.111899","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the mechanisms by which allyl isothiocyanate<span> (AITC) exerts its anticancer effects, the present study investigated the cytotoxic effects of AITC and its metabolites on hepatocellular carcinoma HepG2 cells.</span></div></div><div><h3>Methods</h3><div>The AITC metabolites, <em>S</em>-(<em>N</em>-allylthiocarbamoyl)-L-glutathione (AITC-GSH), <em>N</em>-acetyl-<em>S</em>-(<em>N</em>-allylthiocarbamoyl)-L-cysteine (NAC-AITC), <em>S</em>-(<em>N</em>-allylthiocarbamoyl)-L-cysteinylglycine (AITC-Cys-Gly), and <em>S</em>-(<em>N</em><span>-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.</span></div></div><div><h3>Results</h3><div>AITC, AITC-GSH, and NAC-AITC significantly induced cell cycle arrest in the G<sub>2</sub>/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 G<sub>2</sub>/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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111899"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143421098","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}
Pub Date : 2025-01-01Epub Date: 2024-12-12DOI: 10.1016/j.mrfmmm.2024.111895
Vildan Betul Yenigun , Vasfiye Betul Ucar , Zeynep Betul Sari , Ali Ahmed Azzawri , Yasemin Sena Acar , Muhammed Burak Kaplan , Suleyman Nergiz , Hasan Acar
Background
Head and neck squamous cell carcinomas are the seventh most common cancer accounting for 90 % of malignant neoplasia of the upper respiratory system. KRAS is a very important oncogene, leading to the suppression of apoptosis, and promoting the pathogenesis and development of tumors. MicroRNAs (miRNAs) are highly conserved, small noncoding RNA molecules aberrantly expressed in various pathologies including regulation of tumor and metastasis-associated genes. Variant (rs61764370) of the let-7 miRNA complementary site of KRAS 3’-untranslated region (KRAS-LCS6) has been shown to disrupt the ability of miRNAs to target genes resulting in differential target mRNA and protein expression.
Methods
In this study, the effects of variant complementary site LCS6 of the let-7 miRNA in head and neck cancer were investigated in vitro using laryngeal carcinoma HEp-2 carrying G12V and LCS6 alterations in the KRAS gene. Non-cancer HEK-293 cells were also used as control cells.
Results
G12V mutation in the KRAS gene increases invasion capacity and is specifically active on the ERK pathway associated with metastasis. Alteration in the LCS6 region of the KRAS gene did not show additional effects compared to cells only carrying G12V mutation. Our results also showed that the coexistence of G12V and LCS6 alterations is lethal to specific cell types, UM-SCC-17A laryngeal cancer cells in our case.
Conclusions
The LCS6 region alteration of the KRAS may play a key role in further cancer progression, and more research is needed to fully understand the mechanisms by which the LCS6 alterations promote cancer progression.
{"title":"Evaluation of the simultaneous effects of KRAS G12V and LCS6 alterations on the behavior of head and neck squamous cell carcinoma","authors":"Vildan Betul Yenigun , Vasfiye Betul Ucar , Zeynep Betul Sari , Ali Ahmed Azzawri , Yasemin Sena Acar , Muhammed Burak Kaplan , Suleyman Nergiz , Hasan Acar","doi":"10.1016/j.mrfmmm.2024.111895","DOIUrl":"10.1016/j.mrfmmm.2024.111895","url":null,"abstract":"<div><h3>Background</h3><div><span><span>Head and neck </span>squamous cell carcinomas are the seventh most common cancer accounting for 90 % of malignant neoplasia of the upper respiratory system. </span><span><span>KRAS</span></span><span><span> is a very important oncogene, leading to the suppression of </span>apoptosis<span>, and promoting the pathogenesis and development of tumors. MicroRNAs<span> (miRNAs) are highly conserved, small noncoding RNA molecules aberrantly expressed in various pathologies including regulation of tumor and metastasis-associated genes. Variant (rs61764370) of the let-7 miRNA complementary site of </span></span></span><em>KRAS</em><span> 3’-untranslated region (KRAS-LCS6) has been shown to disrupt the ability of miRNAs to target genes resulting in differential target mRNA and protein expression.</span></div></div><div><h3>Methods</h3><div><span>In this study, the effects of variant complementary site LCS6 of the let-7 miRNA in head and neck cancer were investigated </span><em>in vitro</em><span> using laryngeal carcinoma HEp-2 carrying G12V and LCS6 alterations in the </span><em>KRAS</em> gene. Non-cancer HEK-293 cells were also used as control cells.</div></div><div><h3>Results</h3><div>G12V mutation in the <em>KRAS</em><span> gene increases invasion capacity and is specifically active on the ERK pathway associated with metastasis. Alteration in the LCS6 region of the </span><em>KRAS</em><span> gene did not show additional effects compared to cells only carrying G12V mutation. Our results also showed that the coexistence of G12V and LCS6 alterations is lethal to specific cell types, UM-SCC-17A laryngeal cancer cells in our case.</span></div></div><div><h3>Conclusions</h3><div>The LCS6 region alteration of the <em>KRAS</em> may play a key role in further cancer progression, and more research is needed to fully understand the mechanisms by which the LCS6 alterations promote cancer progression.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111895"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819981","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}
Pub Date : 2025-01-01Epub Date: 2024-11-19DOI: 10.1016/j.mrfmmm.2024.111894
Chao Tan , Li Zhang , Sai Chen , Zhenzhen Tian , Nina Zhou , Yuling Li , Qi Wang , Lu Chen
Gefitinib is a therapeutic agent used to treat lung carcinoma, including non-small cell lung cancer (NSCLC). However, mechanisms underlying NSCLC cell resistance to gefitinib remain largely uncharacterized. In this study, we explored the association between the miR-124–3p/SLC34A2 axis and gefitinib resistance using a series of in vivo and in vitro assays. Data indicated that miR-124–3p is downregulated, while SLC34A2 is upregulated, in gefitinib-resistant NSCLC cells. Overexpression of miR-124–3p reduced NSCLC cell resistance to gefitinib by suppressing cell viability, inducing apoptosis, and decreasing N-cadherin expression. Conversely, inhibiting miR-124–3p in NSCLC cells led to increased cell viability and reduced apoptosis. Overexpression of SLC34A2 in NSCLC cells further heightened gefitinib resistance. In a xenograft mouse model, SLC34A2 overexpression promoted solid tumor growth and metastasis, while miR-124–3p overexpression inhibited these effects. Our results highlight that the interaction between miR-124–3p and SLC34A2 plays an indispensable role in determining gefitinib resistance in NSCLC cells.
{"title":"High expression of SLC34A2 contributes to chemoresistance of non-small cell lung cancer against gefitinib: The critical role of miR-124–3p","authors":"Chao Tan , Li Zhang , Sai Chen , Zhenzhen Tian , Nina Zhou , Yuling Li , Qi Wang , Lu Chen","doi":"10.1016/j.mrfmmm.2024.111894","DOIUrl":"10.1016/j.mrfmmm.2024.111894","url":null,"abstract":"<div><div><span><span>Gefitinib is a therapeutic agent used to treat </span>lung carcinoma<span>, including non-small cell lung cancer (NSCLC). However, mechanisms underlying NSCLC cell resistance to gefitinib remain largely uncharacterized. In this study, we explored the association between the miR-124–3p/SLC34A2 axis and gefitinib resistance using a series of </span></span><em>in vivo</em> and <em>in vitro</em><span><span><span> assays. Data indicated that miR-124–3p is downregulated, while SLC34A2 is upregulated, in gefitinib-resistant NSCLC cells. Overexpression of miR-124–3p reduced NSCLC cell resistance to gefitinib by suppressing </span>cell viability, inducing </span>apoptosis<span><span><span>, and decreasing N-cadherin expression. Conversely, inhibiting miR-124–3p in NSCLC cells led to increased cell viability and reduced apoptosis. Overexpression of SLC34A2 in NSCLC cells further heightened gefitinib resistance. In a </span>xenograft mouse model, SLC34A2 overexpression promoted </span>solid tumor growth and metastasis, while miR-124–3p overexpression inhibited these effects. Our results highlight that the interaction between miR-124–3p and SLC34A2 plays an indispensable role in determining gefitinib resistance in NSCLC cells.</span></span></div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111894"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696286","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}
Recent research has discovered a connection between the AAA+ ATPase PSMC4 (Proteasome 26S Subunit, ATPase 4) and several forms of cancer. However, a detailed analysis of the oncogenic potential of PSMC4 was elusive. In this study, we anticipate PSMC4's potential as a cancer biomarker. We aimed to comprehensively assess the expression profiles, prognostic significance, and relevant cellular pathways associated with it. Through our examination of various types of cancers, PSMC4 is found to be overexpressed. Interestingly, our result finds a positive correlation between PSMC4 overexpression and unfavourable overall survival rates in cancer. Further, we looked into the mutations and copy number amplifications of PSMC4 across various cancers. Our study reveals that missense mutations plays a great role behind the oncogenic potential of PSMC4. Several possible mutation sites are predicted. Interestingly, we found fifteen hotspot mutations in the ATPase domain of PSMC4. Additionally, PSMC4 has shown a high amplification percentage in various cancers. We are additionally attentive to the functional characteristics of the protein PSMC4 across various types of cancer. In the protein-protein interaction analyses, it was found that multiple oncoproteins were directly interacting with PSMC4. The top signaling pathways of PSMC4 also indicate that it plays a crucial role in cancer development. Overall, this study reveals that PSMC4 could be a potential diagnostic and prognostic marker for cancer, making it a promising biomarker and target.
{"title":"The mechanism underlying the oncogenic potential of AAA+ ATPase PSMC4 in cancer is revealed by mutations and copy number amplifications","authors":"Sanjida Mallick , Qurratulain Qamar , Bibhudutta Mishra , Aditi Nayak","doi":"10.1016/j.mrfmmm.2025.111901","DOIUrl":"10.1016/j.mrfmmm.2025.111901","url":null,"abstract":"<div><div><span><span>Recent research has discovered a connection between the AAA+ ATPase<span> PSMC4 (Proteasome 26S Subunit, ATPase 4) and several forms of cancer. However, a detailed analysis of the oncogenic potential of PSMC4 was elusive. In this study, we anticipate PSMC4's potential as a cancer biomarker. We aimed to comprehensively assess the expression profiles, prognostic significance, and relevant cellular pathways associated with it. Through our examination of various types of cancers, PSMC4 is found to be overexpressed. Interestingly, our result finds a positive correlation between PSMC4 overexpression and unfavourable </span></span>overall survival rates in cancer. Further, we looked into the mutations and copy number amplifications of PSMC4 across various cancers. Our study reveals that </span>missense mutations<span><span> plays a great role behind the oncogenic potential of PSMC4. Several possible mutation sites are predicted. Interestingly, we found fifteen hotspot mutations in the ATPase domain of PSMC4. Additionally, PSMC4 has shown a high amplification percentage in various cancers. We are additionally attentive to the functional characteristics of the protein PSMC4 across various types of cancer. In the protein-protein interaction analyses, it was found that multiple </span>oncoproteins<span> were directly interacting with PSMC4. The top signaling pathways of PSMC4 also indicate that it plays a crucial role in cancer development. Overall, this study reveals that PSMC4 could be a potential diagnostic and prognostic marker for cancer, making it a promising biomarker and target.</span></span></div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111901"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464973","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}
Pub Date : 2024-07-01Epub Date: 2024-07-06DOI: 10.1016/j.mrfmmm.2024.111871
Junko Maeda, Piyawan Chailapakul, Takamitsu A. Kato
Chinese hamster-derived cell lines including Chinese hamster lung fibroblasts (V79) have been used as model somatic cell lines in radiation biology and toxicology research for decades and have been instrumental in advancing our understanding of DNA damage response (DDR) mechanisms. Whereas many mutant lines deficient in DDR genes have been generated more than over decades, several key DDR genes such as ATM and ATR have not been established in the Chinese hamster system. Here, we transfected CRISPR/Cas9 vectors targeting Chinese hamster ATM or ATR into V79 cells and investigated whether the isolated clones had the characteristics reported in human and mouse studies. We obtained two clones of ATM knockout cells containing an insertion or deletions in the targeted locus. The ATM knockouts with no detectable ATM protein expression exhibited increased sensitivity to radiation and DNA double strand break inducing agents, cell cycle checkpoint defects and defective chromatid break repair. These are all characteristics of defective ATM function. Among the obtained ATR cells, which contained mutations in both ATR alleles while maintaining normal levels of ATR protein expression, one clone exhibited hypersensitivity to UV and replication stress agents. In the present study, we successfully established CRISPR-Cas9 derived ATM knockout cells. We couldn't knock out the ATR gene but obtained ATR mutant cells. Our results showed that Chinese hamster origin ATM knockout cells and ATR mutant cells could be useful tools for further research to reveal oncogenic functions and effects of developing anti-cancer therapeutics.
{"title":"ATM and ATR gene editing mediated by CRISPR/Cas9 in Chinese Hamster cells","authors":"Junko Maeda, Piyawan Chailapakul, Takamitsu A. Kato","doi":"10.1016/j.mrfmmm.2024.111871","DOIUrl":"10.1016/j.mrfmmm.2024.111871","url":null,"abstract":"<div><p>Chinese hamster-derived cell lines including Chinese hamster lung fibroblasts (V79) have been used as model somatic cell lines in radiation biology and toxicology research for decades and have been instrumental in advancing our understanding of DNA damage response (DDR) mechanisms. Whereas many mutant lines deficient in DDR genes have been generated more than over decades, several key DDR genes such as ATM and ATR have not been established in the Chinese hamster system. Here, we transfected CRISPR/Cas9 vectors targeting Chinese hamster ATM or ATR into V79 cells and investigated whether the isolated clones had the characteristics reported in human and mouse studies. We obtained two clones of ATM knockout cells containing an insertion or deletions in the targeted locus. The ATM knockouts with no detectable ATM protein expression exhibited increased sensitivity to radiation and DNA double strand break inducing agents, cell cycle checkpoint defects and defective chromatid break repair. These are all characteristics of defective ATM function. Among the obtained ATR cells, which contained mutations in both ATR alleles while maintaining normal levels of ATR protein expression, one clone exhibited hypersensitivity to UV and replication stress agents. In the present study, we successfully established CRISPR-Cas9 derived ATM knockout cells. We couldn't knock out the ATR gene but obtained ATR mutant cells. Our results showed that Chinese hamster origin ATM knockout cells and ATR mutant cells could be useful tools for further research to reveal oncogenic functions and effects of developing anti-cancer therapeutics.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"829 ","pages":"Article 111871"},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141638930","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}
Pub Date : 2024-07-01Epub Date: 2024-06-12DOI: 10.1016/j.mrfmmm.2024.111868
Zhengcai Zhu, Tao Li, Honggang Wang, Lianghe Jiao
Background
Emerging data identifies aquaporin 5 (AQP5) as a vital player in many kinds of cancers. Over expression of AQP5 was associated with increased metastasis and poor prognosis, suggesting that AQP5 may facilitate cancer cell proliferation and migration. Our previous studies also showed that AQP3 and AQP5 were highly expressed in triple-negative breast cancer (TNBC) and the expression of AQP3 and AQP5 in TNBC tissue was positive correlated with advanced clinical stage.
Objective
We aim to investigate the role of AQP5 in TNBC oncogenesis and development.
Methods
MDA-MB-231 cells were transfected with siRNA-AQP5 and AQP5 overexpression vector to establish a differential expression system for AQP5. Cell proliferation and apoptosis of MDA-MB-231 cells were detected by CCK-8 (Cell Counting Kit-8) and FCM (flow cytometry), respectively. Cell migration and invasion abilities were evaluated by wound healing assay and transwell assay. The qRT-PCR and western blot assays were used to study the effect of AQP5 expression level on the expression of epithelial-to-mesenchymal transition (EMT) related molecules. The effects of ICG-001, a Wnt/β-catenin signaling pathway inhibitor, on the invasive and migratory capabilities of overexpressed AQP5 cells and downstream molecules were measured.
Results
1. The expression of AQP5 in the MDA-MB-231 cells was significantly higher than that in the MCF-10A cells. 2. Up-regulation of AQP5 significantly promoted the proliferation, migration and invasion of TNBC cells, while inhibited the cell apoptosis; in addition, up-regulation of AQP5 increased the expression of Bcl-2 and decreased the expression of Caspase-3. However, knockdown of AQP5 presented the adverse effects of AQP5 overexpression. 3. Overexpressed AQP5 induced the overexpression of EMT-related factors, which further promoted the migration and invasion of cells. 4. Overexpression of AQP5 could up-regulate the expression of β-catenin in the nucleus followed by increasing the expression levels of downstream genes in Wnt/β-catenin signaling pathway. Moreover, ICG-001, the inhibitor of Wnt/β-catenin signaling pathway, could significantly attenuate the effect of overexpression of AQP5 on cells, further confirming that AQP5 may promote the proliferation, migration and invasion of TNBC cells by activating Wnt/β-catenin signaling pathway.
Conclusions
In the TNBC cells, AQP5 modulates the expression levels of EMT-related proteins through activation of Wnt/β-catenin signaling pathway, thus enhancing the cell proliferation, migration and invasion while inhibiting the cell apoptosis.
{"title":"AQP5 promotes epithelial-mesenchymal transition and tumor growth through activating the Wnt/β-catenin pathway in triple-negative breast cancer","authors":"Zhengcai Zhu, Tao Li, Honggang Wang, Lianghe Jiao","doi":"10.1016/j.mrfmmm.2024.111868","DOIUrl":"10.1016/j.mrfmmm.2024.111868","url":null,"abstract":"<div><h3>Background</h3><p>Emerging data identifies aquaporin 5 (AQP5) as a vital player in many kinds of cancers. Over expression of AQP5 was associated with increased metastasis and poor prognosis, suggesting that AQP5 may facilitate cancer cell proliferation and migration. Our previous studies also showed that AQP3 and AQP5 were highly expressed in triple-negative breast cancer (TNBC) and the expression of AQP3 and AQP5 in TNBC tissue was positive correlated with advanced clinical stage.</p></div><div><h3>Objective</h3><p>We aim to investigate the role of AQP5 in TNBC oncogenesis and development.</p></div><div><h3>Methods</h3><p>MDA-MB-231 cells were transfected with siRNA-AQP5 and AQP5 overexpression vector to establish a differential expression system for AQP5. Cell proliferation and apoptosis of MDA-MB-231 cells were detected by CCK-8 (Cell Counting Kit-8) and FCM (flow cytometry), respectively. Cell migration and invasion abilities were evaluated by wound healing assay and transwell assay. The qRT-PCR and western blot assays were used to study the effect of AQP5 expression level on the expression of epithelial-to-mesenchymal transition (EMT) related molecules. The effects of ICG-001, a Wnt/β-catenin signaling pathway inhibitor, on the invasive and migratory capabilities of overexpressed AQP5 cells and downstream molecules were measured.</p></div><div><h3>Results</h3><p>1. The expression of AQP5 in the MDA-MB-231 cells was significantly higher than that in the MCF-10A cells. 2. Up-regulation of AQP5 significantly promoted the proliferation, migration and invasion of TNBC cells, while inhibited the cell apoptosis; in addition, up-regulation of AQP5 increased the expression of Bcl-2 and decreased the expression of Caspase-3. However, knockdown of AQP5 presented the adverse effects of AQP5 overexpression. 3. Overexpressed AQP5 induced the overexpression of EMT-related factors, which further promoted the migration and invasion of cells. 4. Overexpression of AQP5 could up-regulate the expression of β-catenin in the nucleus followed by increasing the expression levels of downstream genes in Wnt/β-catenin signaling pathway. Moreover, ICG-001, the inhibitor of Wnt/β-catenin signaling pathway, could significantly attenuate the effect of overexpression of AQP5 on cells, further confirming that AQP5 may promote the proliferation, migration and invasion of TNBC cells by activating Wnt/β-catenin signaling pathway.</p></div><div><h3>Conclusions</h3><p>In the TNBC cells, AQP5 modulates the expression levels of EMT-related proteins through activation of Wnt/β-catenin signaling pathway, thus enhancing the cell proliferation, migration and invasion while inhibiting the cell apoptosis.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"829 ","pages":"Article 111868"},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141500041","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}
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