TOP2A induces malignant character of pancreatic cancer through activating β-catenin signaling pathway

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2018-01, Vol.1864 (1), p.197-207
• Main Authors: Pei, Yao-fei, Yin, Xi-min, Liu, Xi-qiang
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; beta Catenin - metabolism; Cell Line, Tumor; Cell Proliferation - genetics; DNA Topoisomerases, Type II - physiology; EMT; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; miR-139; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Poly-ADP-Ribose Binding Proteins - physiology; TOP2A; Wnt Signaling Pathway; β-Catenin
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2017.10.019

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. •TOP2A is up-regulated in pancreatic cancer and is correlated with poor survival.•TOP2A promotes cell proliferation and migration.•TOP2A activates β-catenin pathway in pancreatic cancer.•TOP2A acts as a co-activator ofβ-catenin and activates EMT.•TOP2A is directly regulated by mir-139.