Cancer Res Treat.  2019 Jul;51(3):886-900. 10.4143/crt.2018.375.

Jab1 Silencing Inhibits Proliferation and Sensitizes to Cisplatin in Biliary Tract Cancer

Affiliations
  • 1Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. ohdoyoun@snu.ac.kr
  • 2Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
  • 3Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

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.

Keyword

Jab1; Biliary tract neoplasms; Proliferation; Therapeutic target; Cisplatin

MeSH Terms

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
Cisplatin
PTEN Phosphohydrolase
RNA, Small Interfering
Full Text Links
  • CRT
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2022 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr