Umene Kiyoko, Yanokura Megumi, Banno Kouji, Irie Haruko, Adachi Masataka, Iida Miho, Nakamura Kanako, Nogami Yuya, Masuda Kenta, Kobayashi Yusuke, Tominaga Eiichiro, Aoki Daisuke
Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan.
Int J Oncol. 2015 Apr;46(4):1498-506. doi: 10.3892/ijo.2015.2842. Epub 2015 Jan 22.
Aurora kinase A (AURKA) regulates the cell cycle checkpoint and maintains genomic integrity. AURKA is overexpressed in various malignant tumors and its upregulation induces chromosomal instability, which leads to aneuploidy and cell transformation. To investigate the role of AURKA in endometrial cancer, we evaluated the association of immunohistochemical expression of AURKA with clinicopathological factors. Furthermore, we examined the effects of AURKA inhibition by transfected siRNA in HEC-1B cells on colony-forming ability, invasion and migration capacity, and chemosensitivity. Immunohistochemical staining showed that overexpression of AURKA was significantly associated with tumor grade (P<0.05) and poor histologic differentiation (P<0.05). The recurrence rate also tended to be high in cases with overexpression of AURKA (P<0.1) and these cases also had a tendency for shorter disease-free survival (DFS) (P<0.1). AURKA inhibition in endometrial cancer cell lines significantly decreased cell growth, invasion and migration (P<0.05), and increased chemosensitivity to paclitaxel. We also evaluated the efficacy of a combination of AURKA siRNA and paclitaxel against subcutaneous tumors formed in a nude mouse. After treatment, the tumor volume shrank significantly compared to treatment with paclitaxel only (P<0.05). To our knowledge, this is the first study in endometrial carcinoma to show a correlation between overexpression of AURKA and tumor grade, histological type and sensitivity to paclitaxel. AURKA is a promising therapeutic target in endometrial cancer and the combination therapy with AURKA inhibitors and paclitaxel could be effective for endometrial cancer that is resistant to conventional treatment and has a poor prognosis.
极光激酶A（AURKA）调节细胞周期检查点并维持基因组完整性。AURKA在各种恶性肿瘤中过度表达，其上调会诱导染色体不稳定，进而导致非整倍体和细胞转化。为了研究AURKA在子宫内膜癌中的作用，我们评估了AURKA免疫组化表达与临床病理因素之间的关联。此外，我们检测了在HEC-1B细胞中转染小干扰RNA（siRNA）抑制AURKA对集落形成能力、侵袭和迁移能力以及化疗敏感性的影响。免疫组化染色显示，AURKA的过度表达与肿瘤分级显著相关（P<0.05）以及组织学分化差显著相关（P<0.05）。AURKA过度表达的病例复发率也往往较高（P<0.1），并且这些病例无病生存期（DFS）也往往较短（P<0.1）。抑制子宫内膜癌细胞系中的AURKA可显著降低细胞生长、侵袭和迁移（P<0.05），并增加对紫杉醇的化疗敏感性。我们还评估了AURKA siRNA与紫杉醇联合用药对裸鼠皮下形成肿瘤的疗效。治疗后，与仅用紫杉醇治疗相比，肿瘤体积显著缩小（P<0.05）。据我们所知，这是第一项在子宫内膜癌中显示AURKA过度表达与肿瘤分级、组织学类型以及对紫杉醇敏感性之间存在相关性的研究。AURKA是子宫内膜癌中一个有前景的治疗靶点，AURKA抑制剂与紫杉醇联合治疗可能对耐常规治疗且预后不良的子宫内膜癌有效。
