Jab1 Silencing Inhibits Proliferation and Sensitizes to Cisplatin in Biliary Tract Cancer
- Author:
Ah Rong NAM
1
;
Ji Won KIM
;
Ji Eun PARK
;
Ju Hee BANG
;
Mei Hua JIN
;
Do Youn OH
;
Yung Jue BANG
Author Information
- Publication Type:Original Article
- Keywords: Jab1; Biliary tract neoplasms; Proliferation; Therapeutic target; Cisplatin
- MeSH: Animals; Biliary Tract Neoplasms; Biliary Tract; Cell Line; Cisplatin; DNA Damage; G1 Phase Cell Cycle Checkpoints; Half-Life; Heterografts; Humans; In Vitro Techniques; Mice; Phosphorylation; Prognosis; PTEN Phosphohydrolase; RNA, Small Interfering; Transfection
- From:Cancer Research and Treatment 2019;51(3):886-900
- CountryRepublic of Korea
- Language:English
- Abstract: PURPOSE: Jab1 is a coactivator of c-Jun that enhances the transcriptional function of c-Jun. Jab1 is frequently overexpressed in various cancers and is associatedwith poor prognosis of cancer patients. Thus, Jab1 could be a potential therapeutic target in cancer. However, the role of Jab1 in biliary tract cancer (BTC) has not been studied. MATERIALS AND METHODS: We performed in vitro and in vivo experiments to evaluate the therapeutic potential ofJab1 inhibition in BTC. RESULTS: Among 8 BTC cell lines, many showed higher Jab1 expression levels. In addition, Jab1 silencing by siRNA increased p27 expression levels. SNU478 and HuCCT-1 cells exhibited profound Jab1 knockdown and increased p27 expression by Jab1-specific siRNA transfection. Jab1 silencing induced anti-proliferative and anti-migratory effects and resulted in G1 cell cycle arrest in SNU478 and HuCCT-1 cells. In addition, Jab1 silencing potentiated the anti-proliferative and anti-migratory effects of cisplatin by increasing DNA damage. Interestingly,Jab1 knockdown increased PTEN protein half-life, resulting in increased PTEN expression. In the HuCCT-1 mouse xenograft model, stable knockdown of Jab1 by shRNA also showed anti-proliferative effects in vivo, with decreased Ki-67 expression and AKT phosphorylation and increased Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling and p27 expression. CONCLUSION: Jab1 knockdown demonstrated anti-proliferative and anti-migratory effects in BTC cells by increasing DNA damage and stabilizing PTEN, resulting in G1 cell cycle arrest. In addition, Jab1 silencing potentiated the anti-proliferative effects of cisplatin. Our data suggest that Jab1 may be a potential therapeutic target in BTC that is worthy of further investigations.
