Department of Obstetrics and Gynecology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China.
Department of Oncology, Beijing Chao‑Yang Hospital, Capital Medical University, Beijing 100020, P.R. China.
Int J Oncol. 2020 Jan;56(1):219-231. doi: 10.3892/ijo.2019.4913. Epub 2019 Nov 14.
The oncogene ATPase family AAA domain‑containing protein 2 (ATAD2) has been demonstrated to promote malignancy in a number of different types of tumor; however, its expression and role in ovarian cancer (OC) remain unknown. In the present study, it was demonstrated that ATAD2 acts as both a marker and a driver of cell proliferation in OC. Immunohistochemistry (IHC) and bioinformatics analyses were used to evaluate ATAD2 expression in OC, and multi‑omics integrated analyses were used to dissect which factor resulted in its upregulation. Multiplex IHC assay was used to reveal the specific expression of ATAD2 in proliferating OC cells. CRISPR‑Cas9‑mediated gene editing was performed to investigate the effect of ATAD2 deletion on OC proliferation. The results demonstrated that ATAD2 is elevated in primary OC tissues compared with the adjacent normal tissue and metastases from the stomach. Genetic copy number amplification is a primary cause resulting in upregulation of ATAD2, and this was most frequently observed in OC. High ATAD2 expression was associated with advanced progression and predicted an unfavorable prognosis. ATAD2 could be used to identify cases of OC with a high proliferation signature and could label proliferating cells in OC. CRISPR‑Cas9‑mediated ATAD2 deletion resulted in a significant decrease in both cell proliferation and colony formation ability. Mechanistically, ATAD2‑knockdown resulted in deactivation of the mitogen‑activated protein kinase (MAPK) pathways, particularly the JNK‑MAPK pathway, resulting in suppression of proliferation. Collectively, the data from the present study demonstrated that the ATD2 gene was frequently amplified and protein expression levels were upregulated in OC. Therefore, ATAD2 may serve as an attractive diagnostic and prognostic OC marker, which may be used to identify patients with primary OC, whom are most likely to benefit from ATAD2 gene‑targeted proliferation intervention therapies.
癌基因 ATP 酶家族 AAA 结构域包含蛋白 2（ATAD2）已被证实可促进多种不同类型肿瘤的恶性转化；然而，其在卵巢癌（OC）中的表达和作用尚不清楚。在本研究中，证实 ATAD2 既是 OC 细胞增殖的标志物，也是其驱动因子。采用免疫组织化学（IHC）和生物信息学分析评估 OC 中 ATAD2 的表达，并采用多组学整合分析来剖析导致其上调的因素。采用多重 IHC 检测法揭示 ATAD2 在增殖的 OC 细胞中的特异性表达。通过 CRISPR-Cas9 介导的基因编辑来研究 ATAD2 缺失对 OC 增殖的影响。结果表明，与相邻正常组织和来自胃的转移灶相比，ATAD2 在原发性 OC 组织中上调。基因拷贝数扩增是导致 ATAD2 上调的主要原因，这在 OC 中最为常见。高 ATAD2 表达与晚期进展相关，并预测预后不良。ATAD2 可用于识别 OC 中具有高增殖特征的病例，并可标记 OC 中的增殖细胞。CRISPR-Cas9 介导的 ATAD2 缺失导致细胞增殖和集落形成能力显著下降。机制上，ATAD2 敲低导致丝裂原激活蛋白激酶（MAPK）通路失活，特别是 JNK-MAPK 通路，从而抑制增殖。总之，本研究的数据表明，ATAD2 基因在 OC 中经常扩增，蛋白表达水平上调。因此，ATAD2 可作为一种有吸引力的 OC 诊断和预后标志物，可用于识别最有可能受益于 ATAD2 基因靶向增殖干预治疗的原发性 OC 患者。
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