OncoTargets and Therapy (Sep 2019)
Up-regulated LncRNA-ATB regulates the growth and metastasis of cholangiocarcinoma via miR-200c signals
Abstract
Hai Lin,1,2 Lili Yang,2 Feng Tian,2 Shuang Nie,3 Hailang Zhou,4 Jun Liu,5 Weichang Chen1 1Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People’s Republic of China; 2Department of Gastroenterology, Lin Yi Central Hospital, Linyi, Shandong 276400, People’s Republic of China; 3Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, People’s Republic of China; 4Department of Gastroenterology, Lian Shui County People’s Hospital, Huaian, Jiangsu 223400, People’s Republic of China; 5Department of Pathology, Lin Yi Central Hospital, Linyi, Shandong 276400, People’s Republic of ChinaCorrespondence: Weichang ChenDepartment of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, People’s Republic of ChinaTel +86 1 509 476 9153Email [email protected] and objective: Cholangiocarcinoma (CCA) is a highly aggressive neoplasm featured with regional invasiveness and distant metastasis, which often present a phenotype of epithelial–mesenchymal transition (EMT). Long non-coding RNAs (LncRNAs) are dysregulated during carcinogenesis, and up-regulated LncRNA-activated by TGF-β (Lnc-ATB) supports tumor growth and metastasis via tumor suppressor microRNA 200 (miR-200). However, the role of Lnc-ATB in CCA is unclear.Methods: CCA tissues and non-cancer tissues (n=30) were used to determine the Lnc-ATB and miR-200a/b/c levels. The functions and mechanisms of Lnc-ATB/miR-200 pathway were determined by knockdown of Lnc-ATB via siRNAs in vitro and in vivo.Results: CCA tissues have increased Lnc-ATB and reduced miR-200a/b/c levels, but the down-regulated miR-200c was most prominent. Up-regulated Lnc-ATB significant negatively correlated with miR-200c and predicted advanced TNM stage and more lymph node metastasis of CCA patients. Knockdown of Lnc-ATB in two CCA cell lines HuCCT1 and RBE increased miR-200c levels. The luciferase reporter assay further confirmed the direct binding site of miR-200c in Lnc-ATB. Inhibition of Lnc-ATB significantly impaired cell vitality and induced apoptosis and G0/G1 arrest, which, however, was rescued by miR-200c inhibitor. The ability of migration of CCA cells was also up-regulated by Lnc-ATB but was suppressed by miR-200c. Mechanistically, the cell cycle-related CCND1/CDK2, apoptosis-related BCL-2/caspase-3 and EMT-related E-cadherin/ZEB1/2 were regulated by Lnc-ATB via miR-200c. Knockdown of Lnc-ATB in vivo up-regulated miR-200c signals to inhibit tumor growth with decreased PCNA expression in tumor tissues, which was restored by miR-200c inhibition.Conclusion: Overexpressed Lnc-ATB functioned as an oncogene for CCA growth and metastasis via miR-200 signals.Keywords: Lnc-ATB, miR-200, growth, EMT, cholangiocarcinoma
