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Suppression of hepatocyte proliferation through RORα-mediated IL-6R signaling pathway
핵 수용체 RORα의 IL-6R 신호전달 조절을 통한 간세포 증식 억제 효과

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Authors
김주연
Advisor
이미옥
Major
약학대학 약학과
Issue Date
2017-02
Publisher
서울대학교 대학원
Keywords
RORα
Description
학위논문 (석사)-- 서울대학교 대학원 : 약학과, 2017. 2. 이미옥.
Abstract
Nonalcoholic fatty liver disease (NAFLD) is classified into simple steatosis and steatohepatitis, which can progress to hepatocellular carcinoma. Fat accumulation within hepatocytes results in ROS production and triggers liver inflammation In an inflammatory region of liver, IL-6, which is one of the major inflammtory cytokines, binds to membrane-bound IL-6R on hepatocyte and IL-6R stimulation leads to the activation of JAK/STAT3, and induces upregulation of genes involved in compensatory proliferation. Therefore, inhibition of IL-6R signaling is important for regulation of liver malignancy. Retinoic acid receptor related orphan receptor α (RORα) is related various liver metabolism diseases including NAFLD. Recently, It is reported that RORα could be a potential tumor suppressor gene in liver cancer, but the specific mechanism is elusive. To identify the IL-6 signaling component regulated by RORα, I used RORα overexpression adenovirus in primary mouse hepatocytes. The data showed that RORα overexpression decreased expression of IL-6Rα. Moreover, I observed that RORα overexpression decreased the activation of JAK2 and STAT3, the downstream factors of IL-6Rα. Also, Chromatin Immunoprecipitation followed by sequencing (ChIP-seq) in public database showed five RORα binding signals on the intron region of IL-6Rα gene, and it was identified that RORα bound to one of the five region followed by histone deacetylation by ChIP assay. Next, I tested effects of RORα after partial hepatectomy model. I found that upregulation of IL-6R signaling resulted in facilitating hepatocyte proliferation in liver-specific RORα knockout mice. Also, activation of IL-6R signaling increased diethylnitrosamine (DEN)-induced tumorigenesis in liver-specific RORα knockout mice. These findings revealed that RORα is a novel therapeutic target for compensatory proliferation-induced liver cancer.
Language
English
URI
https://hdl.handle.net/10371/133662
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College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Theses (Master's Degree_약학과)
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