{"title":"USP22 通过去泛素化 MDM2 促进非小细胞肺癌的吉非替尼耐药性并抑制铁变态反应。","authors":"Peng Lu, Zhaoguo Li, Hang Xu","doi":"10.1111/1759-7714.15439","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The emergence of chemoresistance markedly compromised the treatment efficiency of human cancer, including non-small cell lung cancer (NSCLC). In the present study, we aimed to explore the effects of ubiquitin-specific peptidase 22 (USP22) and murine double minute 2 (MDM2) in gefitinib resistance in NSCLC.</p><p><strong>Methods: </strong>Immunohistochemistry (IHC) assay, quantitative real-time polymerase chain reaction (qRT-PCR) assay and western blot assay were carried out to determine the expression of USP22 and MDM2. Transwell assay and flow cytometry analysis were performed to evaluate cell migration and apoptosis. Cell Counting Kit-8 (CCK-8) assay was employed to assess gefitinib resistance. The phenomenon of ferroptosis was estimated by related commercial kits. The oxidized C11-BODIPY fluorescence intensity by C11-BODIPY staining. The relation between USP22 and MDM2 was analyzed by ubiquitination assay and co-immunoprecipitation (Co-IP) assay.</p><p><strong>Results: </strong>USP22 was abnormally upregulated in NSCLC tissues and cells, and USP22 silencing markedly repressed NSCLC cell migration and facilitated apoptosis and ferroptosis. Moreover, our results indicated that ferroptosis could enhance the suppressive effect of gefitinib on NSCLC cells. Besides, USP22 overexpression enhanced gefitinib resistance and ferroptosis protection in NSCLC cells. Mechanically, USP22 stabilized MDM2 and regulated MDM2 expression through deubiquitination of MDM2. MDM2 deficiency partially restored the effects of USP22 on gefitinib resistance and ferroptosis in NSCLC cells. Of note, we validated the promotional effect of USP22 on gefitinib resistance in NSCLC in vivo through establishing the murine xenograft model.</p><p><strong>Conclusion: </strong>USP22/MDM2 promoted gefitinib resistance and inhibited ferroptosis in NSCLC, which might offer a novel strategy for overcoming gefitinib resistance in NSCLC.</p>","PeriodicalId":23338,"journal":{"name":"Thoracic Cancer","volume":null,"pages":null},"PeriodicalIF":2.3000,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"USP22 promotes gefitinib resistance and inhibits ferroptosis in non-small cell lung cancer by deubiquitination of MDM2.\",\"authors\":\"Peng Lu, Zhaoguo Li, Hang Xu\",\"doi\":\"10.1111/1759-7714.15439\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The emergence of chemoresistance markedly compromised the treatment efficiency of human cancer, including non-small cell lung cancer (NSCLC). In the present study, we aimed to explore the effects of ubiquitin-specific peptidase 22 (USP22) and murine double minute 2 (MDM2) in gefitinib resistance in NSCLC.</p><p><strong>Methods: </strong>Immunohistochemistry (IHC) assay, quantitative real-time polymerase chain reaction (qRT-PCR) assay and western blot assay were carried out to determine the expression of USP22 and MDM2. Transwell assay and flow cytometry analysis were performed to evaluate cell migration and apoptosis. Cell Counting Kit-8 (CCK-8) assay was employed to assess gefitinib resistance. The phenomenon of ferroptosis was estimated by related commercial kits. The oxidized C11-BODIPY fluorescence intensity by C11-BODIPY staining. The relation between USP22 and MDM2 was analyzed by ubiquitination assay and co-immunoprecipitation (Co-IP) assay.</p><p><strong>Results: </strong>USP22 was abnormally upregulated in NSCLC tissues and cells, and USP22 silencing markedly repressed NSCLC cell migration and facilitated apoptosis and ferroptosis. Moreover, our results indicated that ferroptosis could enhance the suppressive effect of gefitinib on NSCLC cells. Besides, USP22 overexpression enhanced gefitinib resistance and ferroptosis protection in NSCLC cells. Mechanically, USP22 stabilized MDM2 and regulated MDM2 expression through deubiquitination of MDM2. MDM2 deficiency partially restored the effects of USP22 on gefitinib resistance and ferroptosis in NSCLC cells. Of note, we validated the promotional effect of USP22 on gefitinib resistance in NSCLC in vivo through establishing the murine xenograft model.</p><p><strong>Conclusion: </strong>USP22/MDM2 promoted gefitinib resistance and inhibited ferroptosis in NSCLC, which might offer a novel strategy for overcoming gefitinib resistance in NSCLC.</p>\",\"PeriodicalId\":23338,\"journal\":{\"name\":\"Thoracic Cancer\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2024-09-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Thoracic Cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/1759-7714.15439\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Thoracic Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/1759-7714.15439","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
USP22 promotes gefitinib resistance and inhibits ferroptosis in non-small cell lung cancer by deubiquitination of MDM2.
Background: The emergence of chemoresistance markedly compromised the treatment efficiency of human cancer, including non-small cell lung cancer (NSCLC). In the present study, we aimed to explore the effects of ubiquitin-specific peptidase 22 (USP22) and murine double minute 2 (MDM2) in gefitinib resistance in NSCLC.
Methods: Immunohistochemistry (IHC) assay, quantitative real-time polymerase chain reaction (qRT-PCR) assay and western blot assay were carried out to determine the expression of USP22 and MDM2. Transwell assay and flow cytometry analysis were performed to evaluate cell migration and apoptosis. Cell Counting Kit-8 (CCK-8) assay was employed to assess gefitinib resistance. The phenomenon of ferroptosis was estimated by related commercial kits. The oxidized C11-BODIPY fluorescence intensity by C11-BODIPY staining. The relation between USP22 and MDM2 was analyzed by ubiquitination assay and co-immunoprecipitation (Co-IP) assay.
Results: USP22 was abnormally upregulated in NSCLC tissues and cells, and USP22 silencing markedly repressed NSCLC cell migration and facilitated apoptosis and ferroptosis. Moreover, our results indicated that ferroptosis could enhance the suppressive effect of gefitinib on NSCLC cells. Besides, USP22 overexpression enhanced gefitinib resistance and ferroptosis protection in NSCLC cells. Mechanically, USP22 stabilized MDM2 and regulated MDM2 expression through deubiquitination of MDM2. MDM2 deficiency partially restored the effects of USP22 on gefitinib resistance and ferroptosis in NSCLC cells. Of note, we validated the promotional effect of USP22 on gefitinib resistance in NSCLC in vivo through establishing the murine xenograft model.
Conclusion: USP22/MDM2 promoted gefitinib resistance and inhibited ferroptosis in NSCLC, which might offer a novel strategy for overcoming gefitinib resistance in NSCLC.
期刊介绍：
Thoracic Cancer aims to facilitate international collaboration and exchange of comprehensive and cutting-edge information on basic, translational, and applied clinical research in lung cancer, esophageal cancer, mediastinal cancer, breast cancer and other thoracic malignancies. Prevention, treatment and research relevant to Asia-Pacific is a focus area, but submissions from all regions are welcomed. The editors encourage contributions relevant to prevention, general thoracic surgery, medical oncology, radiology, radiation medicine, pathology, basic cancer research, as well as epidemiological and translational studies in thoracic cancer. Thoracic Cancer is the official publication of the Chinese Society of Lung Cancer, International Chinese Society of Thoracic Surgery and is endorsed by the Korean Association for the Study of Lung Cancer and the Hong Kong Cancer Therapy Society.
The Journal publishes a range of article types including: Editorials, Invited Reviews, Mini Reviews, Original Articles, Clinical Guidelines, Technological Notes, Imaging in thoracic cancer, Meeting Reports, Case Reports, Letters to the Editor, Commentaries, and Brief Reports.
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