Browse

Bile acid-mediated induction of hepatic stellate cell activation and invasion via Mcl-1 and COX-2 in hypoxic conditions
저산소조건에서 담즙산이 Mcl-1 및 COX-2 매개 간성상세포의 활성화에 미치는 영향

Cited 0 time in Web of Science Cited 0 time in Scopus
Authors
최원묵
Advisor
윤정환
Major
의과대학 의학과
Issue Date
2015-02
Publisher
서울대학교 대학원
Keywords
hepatic stellate cellbile acidCyclooxygenase-2Mcl-1hypoxia
Description
학위논문 (석사)-- 서울대학교 대학원 : 의학과, 2015. 2. 윤정환.
Abstract
Background: Activated hepatic stellate cells (HSCs) are the major subtype of stromal cells in the liver tumor microenvironment which can promote the growth and migration of hepatocellular carcinoma (HCC) cells. Indeed, senescent and cancer-associated fibroblasts express numerous inflammatory and tumor promoting factors that are collectively referred to as the senescence-associated secretory phenotype (SASP). In the present study, we investigated the mechanisms of bile acid-mediated induction of HSC activation as the SASP in hypoxic conditions.
Methods: The immortalized human stellate cells (LX-2 cells) were used in this study. Invasion assay were done to evaluate the invasion of HSCs either in a normoxic or hypoxic conditions. IL-8 mRNA was quantitated using real-time PCR. To investigate the mechanisms, western blot analyses were performed either in a normoxic or hypoxic conditions.
Results: Bile acid significantly increased the invasion of HSCs in hypoxic conditions as compared to that in normoxic conditions by IL-8 expression, which is an inflammatory cytokine involved in tumor promotion and key component of the SASP. Bile acid increased protein expressions of the mesechymal markers including α-SMA and vimentin in HSCs. Moreover, bile acid increased the protein expressions of Mcl-1 and cyclooxygenase-2 (COX-2) in HSCs. The inhibitors of either Mcl-1 induction by siRNA transfection or COX-2 activity by celecoxib decreased the bile acid-mediated HSC invasion in hypoxic conditions. Mcl-1 and COX-2 induction was found to be due to transcriptional enhancement dependent on TGR-5 activation.
Conclusions: Bile acid-mediated induction of HSC activation and invasion as the SASP was due to TGR-5 dependent overexpression of Mcl-1 and COX-2, which may lead to HCC progression in hypoxic conditions.
Language
English
URI
http://hdl.handle.net/10371/132730
Files in This Item:
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Theses (Master's Degree_의학과)
  • mendeley

Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse