Top2a, also known as DNA topoisomerase II alpha, is a crucial enzyme in DNA replication and cell proliferation [1,3,4,5,6,7]. It resolves topological problems during DNA replication, transcription, and chromatin remodeling, playing a vital role in cell cycle progression. It is associated with multiple signaling pathways such as AKT/mTOR, Wnt/β -catenin, and NF -κB, which are involved in various biological processes and disease development [1,5,8]. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, have been used to study its functions.

In ovarian cancer, TOP2A knockdown inhibited cell proliferation, with cells entering G1 phase arrest and apoptosis, and it was confirmed to regulate cell proliferation and cell cycle through the AKT/mTOR pathway in rescue assays. Mouse model experiments further affirmed its role as a driver of ovarian cancer cell proliferation [1]. In hepatocellular carcinoma, inhibition of EZH2 and TOP2A in vitro induced cellular senescence and inhibited cell proliferation, and in vivo tumorigenesis assays showed that EZH2 and TOP2A knockdown inhibited tumorigenesis by inducing cellular senescence [2]. In medulloblastoma, knockdown of TOP2A inhibited cell proliferation, migration, and invasion, and reduced radioresistance. The Wnt/β -catenin signaling pathway may be involved in these processes [5]. In hepatocellular carcinoma, silencing TOP2A enhanced cells' sensitivity to regorafenib, and TOP2A inhibition by doxorubicin or epirubicin synergized with regorafenib to suppress the growth of sorafenib-resistant tumors [6]. In mice, TOP2A-deficient embryos had impaired trophectoderm differentiation, embryonic mitochondrial function, and developmental rate [9].

In conclusion, model-based research has revealed that Top2a is essential for DNA replication, cell proliferation, and cell cycle regulation. KO/CKO mouse models have contributed to understanding its role in diseases such as ovarian cancer, hepatocellular carcinoma, medulloblastoma, and recurrent spontaneous abortion. These findings provide insights into potential therapeutic strategies targeting Top2a in these disease areas.

References:

1. Zhang, Kaiwen, Zheng, Xingyu, Sun, Yiqing, Tian, Wenyan, Wang, Yingmei. 2024. TOP2A modulates signaling via the AKT/mTOR pathway to promote ovarian cancer cell proliferation. In Cancer biology & therapy, 25, 2325126. doi:10.1080/15384047.2024.2325126. https://pubmed.ncbi.nlm.nih.gov/38445610/

2. Wang, Ke, Jiang, Xunliang, Jiang, Yu, Li, Jipeng, Zhang, Rui. 2023. EZH2-H3K27me3-mediated silencing of mir-139-5p inhibits cellular senescence in hepatocellular carcinoma by activating TOP2A. In Journal of experimental & clinical cancer research : CR, 42, 320. doi:10.1186/s13046-023-02855-2. https://pubmed.ncbi.nlm.nih.gov/38008711/

3. Borella, Fulvio, Fucina, Stefano, Seminara, Ylenia, Marozio, Luca, Cosma, Stefano. 2024. Targeting TOP2A in Ovarian Cancer: Biological and Clinical Implications. In Current oncology (Toronto, Ont.), 31, 8054-8074. doi:10.3390/curroncol31120594. https://pubmed.ncbi.nlm.nih.gov/39727717/

4. Tian, Tian, Bu, Min, Chen, Xu, Li, Qing, Huang, Jun. 2020. The ZATT-TOP2A-PICH Axis Drives Extensive Replication Fork Reversal to Promote Genome Stability. In Molecular cell, 81, 198-211.e6. doi:10.1016/j.molcel.2020.11.007. https://pubmed.ncbi.nlm.nih.gov/33296677/

5. Zhang, Yufeng, Yang, Haiyan, Wang, Liwen, Xiao, Zhiqing, Xue, Xiaoying. 2022. TOP2A correlates with poor prognosis and affects radioresistance of medulloblastoma. In Frontiers in oncology, 12, 918959. doi:10.3389/fonc.2022.918959. https://pubmed.ncbi.nlm.nih.gov/35912241/

6. Wang, Zongwen, Zhu, Qiankun, Li, Xiaodong, Dong, Xiaoqun, Zhai, Bo. 2022. TOP2A inhibition reverses drug resistance of hepatocellular carcinoma to regorafenib. In American journal of cancer research, 12, 4343-4360. doi:. https://pubmed.ncbi.nlm.nih.gov/36225636/

7. Wang, Tim, Wei, Jenny J, Sabatini, David M, Lander, Eric S. 2013. Genetic screens in human cells using the CRISPR-Cas9 system. In Science (New York, N.Y.), 343, 80-4. doi:10.1126/science.1246981. https://pubmed.ncbi.nlm.nih.gov/24336569/

8. Fu, Huijia, Tan, Wang, Chen, Zhi, Qi, Hongbo, Liu, Xiru. 2022. TOP2A deficit-induced abnormal decidualization leads to recurrent implantation failure via the NF-κB signaling pathway. In Reproductive biology and endocrinology : RB&E, 20, 142. doi:10.1186/s12958-022-01013-1. https://pubmed.ncbi.nlm.nih.gov/36138481/

9. Duan, Yuhan, Fu, Huijia, Huang, Jiayu, Liu, Linhong, Liu, Xiru. 2022. TOP2A deficiency leads to human recurrent spontaneous abortion and growth retardation of mouse pre-implantation embryos. In Molecular medicine (Cambridge, Mass.), 28, 165. doi:10.1186/s10020-022-00592-4. https://pubmed.ncbi.nlm.nih.gov/36585615/