{"title":"A positive feedback loop of SRSF9/USP22/ZEB1 promotes the progression of ovarian cancer.","authors":"Jing Wang, Ming Hu, Jie Min, Xin Li","doi":"10.1080/15384047.2024.2427415","DOIUrl":null,"url":null,"abstract":"<p><p>Ovarian cancer (OC) is recognized as the most lethal type of gynecological malignancy, making treatment options challenging. Discovering novel therapeutic targets will benefit OC patients. This study aimed to reveal the mechanism by which SRSF9 regulates OC progression. Cell proliferation was determined via CCK-8 assays, whereas cell migration and invasion were monitored via Transwell assays. Western blotting and qPCR assays were used to detect protein and mRNA alterations. RNA pull-down, RNA immunoprecipitation (RIP), and actinomycin D experiments were performed to investigate the relationships between SRSF9 and USP22. Co-IP was used to validate the interaction between USP22 and ZEB1. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were used to verify the regulatory effect of ZEB1 on the transcription of SRSF9. Subcutaneous xenograft models were established to evaluate the impact of SRSF9 on tumor development. Knockdown of SRSF9 significantly suppressed the proliferation, invasion, migration, tumorigenicity, and epithelial‒mesenchymal transition (EMT) of OC cells. SRSF9 can bind to USP22 mRNA, increasing its stability. Moreover, the overexpression of USP22 reversed the impact of SRSF9 silencing on malignant phenotypes. USP22 can mediate the deubiquitination of ZEB1, thereby enhancing the progression of OC. Furthermore, ZEB1 upregulated SRSF9 expression through transcriptional activation, thus establishing a positive feedback loop. SRSF9 enhanced the malignant characteristics of OC through a positive feedback loop of SRSF9/USP22/ZEB1. This functional circuit may help in the development of novel therapeutic approaches for treating OC.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"25 1","pages":"2427415"},"PeriodicalIF":4.4000,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559372/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Biology & Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/15384047.2024.2427415","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/12 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Ovarian cancer (OC) is recognized as the most lethal type of gynecological malignancy, making treatment options challenging. Discovering novel therapeutic targets will benefit OC patients. This study aimed to reveal the mechanism by which SRSF9 regulates OC progression. Cell proliferation was determined via CCK-8 assays, whereas cell migration and invasion were monitored via Transwell assays. Western blotting and qPCR assays were used to detect protein and mRNA alterations. RNA pull-down, RNA immunoprecipitation (RIP), and actinomycin D experiments were performed to investigate the relationships between SRSF9 and USP22. Co-IP was used to validate the interaction between USP22 and ZEB1. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were used to verify the regulatory effect of ZEB1 on the transcription of SRSF9. Subcutaneous xenograft models were established to evaluate the impact of SRSF9 on tumor development. Knockdown of SRSF9 significantly suppressed the proliferation, invasion, migration, tumorigenicity, and epithelial‒mesenchymal transition (EMT) of OC cells. SRSF9 can bind to USP22 mRNA, increasing its stability. Moreover, the overexpression of USP22 reversed the impact of SRSF9 silencing on malignant phenotypes. USP22 can mediate the deubiquitination of ZEB1, thereby enhancing the progression of OC. Furthermore, ZEB1 upregulated SRSF9 expression through transcriptional activation, thus establishing a positive feedback loop. SRSF9 enhanced the malignant characteristics of OC through a positive feedback loop of SRSF9/USP22/ZEB1. This functional circuit may help in the development of novel therapeutic approaches for treating OC.
期刊介绍：
Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.
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