Department of General Surgery, Shanghai First People's Hospital Affiliated to Shanghai JiaoTong University, Shanghai 200080, PR China; Department of Hepatobiliary-Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang Province 310014, PR China.
Department of Hepatobiliary and Minimally Invasive Surgery, Hunan Provincial People's Hospital, Changsha, Hunan Province 410005, PR China.
Biochim Biophys Acta Mol Basis Dis. 2018 Jan;1864(1):197-207. doi: 10.1016/j.bbadis.2017.10.019. Epub 2017 Oct 16.
It has been reported that Topoisomerase II alpha (TOP2A) could induce tumor development and progression in many cancer types. Herein, through analysis of different independent cohorts, we found TOP2A was up-regulated in pancreatic cancer as compared with non-tumor tissues. Moreover, the up-regulation of TOP2A was significantly correlated with tumor metastasis and shorter survival in patients with pancreatic cancer. Knockdown of TOP2A in pancreatic cancer cell lines inhibited cell proliferation and migration. Furthermore, bioinformatics analysis revealed TOP2A activatesβ-catenin pathway in pancreatic cancer. Mechanistically, we demonstrated TOP2A acts as a co-activator ofβ-catenin and activates EMT process. Further investigation showed TOP2A was a direct target of mir-139, which was validated by dual-luciferase reporter gene assay. The effects of mir-139 on pancreatic cancer were also mechanistically, functionally and clinically investigated. Taken together, our research identified a novel miR-139\TOP2A\β-catenin axis driving the malignant progression of pancreatic cancer.
已有报道称拓扑异构酶 IIα（TOP2A）可诱导多种癌症类型的肿瘤发生和发展。在此，通过对不同独立队列的分析，我们发现与非肿瘤组织相比，TOP2A 在胰腺癌中呈上调表达。此外，TOP2A 的上调与胰腺癌患者的肿瘤转移和生存时间缩短显著相关。在胰腺癌细胞系中敲低 TOP2A 可抑制细胞增殖和迁移。此外，生物信息学分析表明 TOP2A 在胰腺癌中激活β-连环蛋白通路。机制上，我们证明 TOP2A 作为β-连环蛋白的共激活因子，激活 EMT 过程。进一步的研究表明 TOP2A 是 mir-139 的直接靶点，这通过双荧光素酶报告基因检测得到了验证。通过双荧光素酶报告基因检测也验证了 mir-139 对胰腺癌的作用是通过机制、功能和临床研究证实的。综上所述，我们的研究确定了一个新的 miR-139\TOP2A\β-连环蛋白轴，驱动胰腺癌的恶性进展。
