卵巢癌增殖标志物ATAD2通过MYBL2调控有丝分裂进程促进卵巢肿瘤恶性增殖的分子机制研究

卵巢癌是女性生殖系统肿瘤中致死率最高的肿瘤。课题组2020最新成果揭示卵巢癌中存在ATAD2基因拷贝数的特异性高扩增，并且作为一个新发现的卵巢癌增殖标志物和调控因子，ATAD2在卵巢癌细胞增殖过程中发挥关键作用，提示ATAD2是一个潜在的卵巢癌治疗靶点。ATAD2调控肿瘤增殖的分子机制依然不明，项目前期发现卵巢癌ATAD2可以显著调控增殖调控因子MYBL2的表达，提示ATAD2通过MYBL2调控增殖。MYBL2是一个有丝分裂调控因子，通过调控G2/M基因转录参与有丝分裂进程及染色体基因组不稳定性调控。据此，我们提出假说：ATAD2通过上调MYBL2激活下游G2/M靶基因表达，进而调控有丝分裂速率和染色体基因组不稳定性，导致卵巢癌增殖速率及异质化水平的增加，共同促进卵巢癌的恶性增殖。项目拟在细胞、小鼠和临床标本三个水平，从有丝分裂角度，深入揭示ATAD2通过MYBL2调控卵巢增殖的分子机制。

Ovarian cancer is the most lethal tumor of the female reproductive system. Our latest report in 2020 revealed that the copy number of ATAD2 gene is specifically high-amplified in ovarian cancer, and that as a newly discovered marker and regulatory factor of ovarian cancer proliferation, ATAD2 plays a key role in regulating ovarian cancer proliferation, suggesting that ATAD2 is a potential therapeutic target for ovarian cancer treatment. The molecular mechanism by which ATAD2 regulates tumor proliferation is still unknown. We found that ATAD2 significantly up-regulated MYBL2 expression, indicating that ATAD2 may regulate proliferation via MYBL2. MYBL2 is a mitotic regulatory factor and is involved in regulation of mitotic process and chromosomal genomic instability through transcriptional regulation of targeted G2/M genes. Accordingly, we hypothesize that ATAD2 regulates the mitotic rate and chromosomal genomic instability via MYBL2-mediated G2/M gene transcription, leading to the increase of the proliferation rate and heterogeneous level in ovarian cancer, which jointly promote the malignant progression of ovarian cancer. This project intends to reveal the molecular mechanism by which ATAD2 regulates ovarian proliferation via MYBL2–mediated mitosis regulation at the cell, mouse and clinical levels.