TOP2A 通过 AKT/mTOR 通路调节信号,促进卵巢癌细胞增殖。

IF 4.4 4区 医学 Q2 ONCOLOGY Cancer Biology & Therapy Pub Date : 2024-12-31 Epub Date: 2024-03-06 DOI:10.1080/15384047.2024.2325126
Kaiwen Zhang, Xingyu Zheng, Yiqing Sun, Xinyu Feng, Xirong Wu, Wenlu Liu, Chao Gao, Ye Yan, Wenyan Tian, Yingmei Wang
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引用次数: 0

摘要

卵巢癌(OC)是一种妇科恶性肿瘤,与女性生殖道的其他癌症相比,卵巢癌患者的预后更差。拓扑异构酶 II α(TOP2A)通常被认为是一种与多种癌症的恶性疾病进展相关的致癌基因,但它在卵巢癌中的机理功能尚未得到确定。我们通过在线数据库、临床样本、体外和体内实验探索了TOP2A在OC中的作用。对公共数据库的初步分析显示,患者样本中与 OC 相关的 TOP2A 高表达与较差的预后有关。这一点在临床样本中得到了证实,与健康组织相比,OC 中的 TOP2A 表达更高。Kaplan-Meier分析进一步表明,TOP2A表达水平越高,OC患者的预后越差。在体外,TOP2A 基因敲除可抑制 OC 细胞的增殖,使细胞进入 G1 期停滞并随之凋亡。在挽救实验中,TOP2A被证实通过AKT/mTOR通路的活性调节细胞增殖和细胞周期。小鼠模型实验进一步证实了 TOP2A 在 OC 细胞增殖中的关键驱动作用。这些数据提供了强有力的证据,支持 TOP2A 成为与 OC 进展和不良预后相关的致癌介质和预后生物标志物。在机理层面,TOP2A 可通过 AKT/mTOR 通路调节控制肿瘤细胞的生长。这些初步结果为今后的研究奠定了基础,有助于探索基于TOP2A抑制剂的联合治疗方案在铂耐药复发性OC患者中的应用。
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TOP2A modulates signaling via the AKT/mTOR pathway to promote ovarian cancer cell proliferation.

Ovarian cancer (OC) is a form of gynecological malignancy that is associated with worse patient outcomes than any other cancer of the female reproductive tract. Topoisomerase II α (TOP2A) is commonly regarded as an oncogene that is associated with malignant disease progression in a variety of cancers, its mechanistic functions in OC have yet to be firmly established. We explored the role of TOP2A in OC through online databases, clinical samples, in vitro and in vivo experiments. And initial analyses of public databases revealed high OC-related TOP2A expression in patient samples that was related to poorer prognosis. This was confirmed by clinical samples in which TOP2A expression was elevated in OC relative to healthy tissue. Kaplan-Meier analyses further suggested that higher TOP2A expression levels were correlated with worse prognosis in OC patients. In vitro, TOP2A knockdown resulted in the inhibition of OC cell proliferation, with cells entering G1 phase arrest and undergoing consequent apoptotic death. In rescue assays, TOP2A was confirmed to regulate cell proliferation and cell cycle through AKT/mTOR pathway activity. Mouse model experiments further affirmed the key role that TOP2A plays as a driver of OC cell proliferation. These data provide strong evidence supporting TOP2A as an oncogenic mediator and prognostic biomarker related to OC progression and poor outcomes. At the mechanistic level, TOP2A can control tumor cell growth via AKT/mTOR pathway modulation. These preliminary results provide a foundation for future research seeking to explore the utility of TOP2A inhibitor-based combination treatment regimens in platinum-resistant recurrent OC patients.

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来源期刊
Cancer Biology & Therapy
Cancer Biology & Therapy 医学-肿瘤学
CiteScore
7.00
自引率
0.00%
发文量
60
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.
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