Thaís Moré Milan, Gabriel da Silva, Lucas Oliveira Sousa, Andréia Machado Leopoldino
{"title":"鞘氨醇激酶 2 通过 p53 调节 miR-205 和 miR-296 来控制口腔鳞状细胞癌的侵袭性表型。","authors":"Thaís Moré Milan, Gabriel da Silva, Lucas Oliveira Sousa, Andréia Machado Leopoldino","doi":"10.1016/j.ajpath.2024.09.009","DOIUrl":null,"url":null,"abstract":"<p><p>Alterations in microRNAs, p53, and sphingolipid metabolism have been associated with head and neck squamous cell carcinoma (HNSCC). However, sphingosine kinase 2, a critical enzyme in sphingolipid metabolism, is poorly understood in HNSCC. Our aim was to investigate how SK2 and p53 interact to regulate miR-205 and miR-296. Analysis of small-RNA-seq data from non-tumor oral keratinocytes with SK2 overexpression (NOK-SK2) compared to NOK-control (NOK- Ø) revealed differential expression of more than 100 miRNAs being half regulated by p53. The expression of miR-205 was downregulated, and miR-296 was upregulated in NOK-SK2 cells; however, cells with SK2 knockdown and p53 overexpression showed an opposite profile. Proteins involved in miRNA biogenesis were increased in NOK-SK2 cells while their levels were decreased in NOK-SK2 cells with p53 overexpression. miR-205 mimic and miR-296 inhibitor decreased the aggressiveness and cancer stem-like cells in oral keratinocytes and oral carcinoma cells with SK2 deregulation. Overexpression of miR-205 in HN12-SK2 cells decreased tumor formation capacity and NOK-SK2 cells abrogated the tumor growth in mice. Our results indicate crosstalk between SK2 and p53 in regulating miR-205 and miR-296, which could be potential targets for HNSCC therapy.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7000,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Sphingosine kinase 2 controls the aggressive phenotype of oral squamous cell carcinoma by regulating miR-205 and miR-296 through p53.\",\"authors\":\"Thaís Moré Milan, Gabriel da Silva, Lucas Oliveira Sousa, Andréia Machado Leopoldino\",\"doi\":\"10.1016/j.ajpath.2024.09.009\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Alterations in microRNAs, p53, and sphingolipid metabolism have been associated with head and neck squamous cell carcinoma (HNSCC). However, sphingosine kinase 2, a critical enzyme in sphingolipid metabolism, is poorly understood in HNSCC. Our aim was to investigate how SK2 and p53 interact to regulate miR-205 and miR-296. Analysis of small-RNA-seq data from non-tumor oral keratinocytes with SK2 overexpression (NOK-SK2) compared to NOK-control (NOK- Ø) revealed differential expression of more than 100 miRNAs being half regulated by p53. The expression of miR-205 was downregulated, and miR-296 was upregulated in NOK-SK2 cells; however, cells with SK2 knockdown and p53 overexpression showed an opposite profile. Proteins involved in miRNA biogenesis were increased in NOK-SK2 cells while their levels were decreased in NOK-SK2 cells with p53 overexpression. miR-205 mimic and miR-296 inhibitor decreased the aggressiveness and cancer stem-like cells in oral keratinocytes and oral carcinoma cells with SK2 deregulation. Overexpression of miR-205 in HN12-SK2 cells decreased tumor formation capacity and NOK-SK2 cells abrogated the tumor growth in mice. Our results indicate crosstalk between SK2 and p53 in regulating miR-205 and miR-296, which could be potential targets for HNSCC therapy.</p>\",\"PeriodicalId\":7623,\"journal\":{\"name\":\"American Journal of Pathology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2024-10-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American Journal of Pathology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ajpath.2024.09.009\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PATHOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ajpath.2024.09.009","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
Sphingosine kinase 2 controls the aggressive phenotype of oral squamous cell carcinoma by regulating miR-205 and miR-296 through p53.
Alterations in microRNAs, p53, and sphingolipid metabolism have been associated with head and neck squamous cell carcinoma (HNSCC). However, sphingosine kinase 2, a critical enzyme in sphingolipid metabolism, is poorly understood in HNSCC. Our aim was to investigate how SK2 and p53 interact to regulate miR-205 and miR-296. Analysis of small-RNA-seq data from non-tumor oral keratinocytes with SK2 overexpression (NOK-SK2) compared to NOK-control (NOK- Ø) revealed differential expression of more than 100 miRNAs being half regulated by p53. The expression of miR-205 was downregulated, and miR-296 was upregulated in NOK-SK2 cells; however, cells with SK2 knockdown and p53 overexpression showed an opposite profile. Proteins involved in miRNA biogenesis were increased in NOK-SK2 cells while their levels were decreased in NOK-SK2 cells with p53 overexpression. miR-205 mimic and miR-296 inhibitor decreased the aggressiveness and cancer stem-like cells in oral keratinocytes and oral carcinoma cells with SK2 deregulation. Overexpression of miR-205 in HN12-SK2 cells decreased tumor formation capacity and NOK-SK2 cells abrogated the tumor growth in mice. Our results indicate crosstalk between SK2 and p53 in regulating miR-205 and miR-296, which could be potential targets for HNSCC therapy.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.