A positive feedback loop of SRSF9/USP22/ZEB1 promotes the progression of ovarian cancer.

IF 4.4 4区医学 Q2 ONCOLOGY Cancer Biology & Therapy Pub Date : 2024-12-31 Epub Date: 2024-11-12 DOI:10.1080/15384047.2024.2427415

Jing Wang, Ming Hu, Jie Min, Xin Li

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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.

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SRSF9/USP22/ZEB1的正反馈回路促进了卵巢癌的进展。

卵巢癌（OC）是公认的致死率最高的妇科恶性肿瘤，因此治疗方案充满挑战。发现新的治疗靶点将使卵巢癌患者受益。本研究旨在揭示SRSF9调控OC进展的机制。细胞增殖通过CCK-8检测法确定，而细胞迁移和侵袭则通过Transwell检测法监测。采用 Western 印迹和 qPCR 方法检测蛋白质和 mRNA 的变化。为了研究 SRSF9 和 USP22 之间的关系，进行了 RNA 拉取、RNA 免疫沉淀（RIP）和放线菌素 D 实验。Co-IP 用于验证 USP22 和 ZEB1 之间的相互作用。染色质免疫沉淀（ChIP）和双荧光素酶报告实验用于验证 ZEB1 对 SRSF9 转录的调控作用。建立皮下异种移植模型以评估SRSF9对肿瘤发生的影响。敲除SRSF9能显著抑制OC细胞的增殖、侵袭、迁移、致瘤性和上皮-间质转化（EMT）。SRSF9能与USP22 mRNA结合，增加其稳定性。此外，USP22的过表达逆转了SRSF9沉默对恶性表型的影响。USP22 可以介导 ZEB1 的去泛素化，从而促进 OC 的进展。此外，ZEB1通过转录激活上调SRSF9的表达，从而建立了一个正反馈回路。SRSF9通过SRSF9/USP22/ZEB1的正反馈回路增强了OC的恶性特征。这一功能回路可能有助于开发治疗OC的新型疗法。

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来源期刊

Cancer Biology & Therapy 医学-肿瘤学

CiteScore

7.00

自引率

0.00%

发文量

审稿时长

2.3 months

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.