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Predominant Activation of JAK/STAT3 Pathway by Interleukin-6 Is Implicated in Hepatocarcinogenesis

Authors
 In Hye Jung  ;  Jeffrey Hyun-Kyu Choi  ;  Yong-Yoon Chung  ;  Ga-Lam Lim  ;  Young-Nyun Park  ;  Seung Woo Park 
Citation
 NEOPLASIA, Vol.17(7) : 586-597, 2015 
Journal Title
 NEOPLASIA 
ISSN
 1522-8002 
Issue Date
2015
MeSH
Aminopyridines/pharmacology ; Animals ; Carcinoma, Hepatocellular/pathology* ; Cell Transformation, Neoplastic ; Cyclic S-Oxides/pharmacology ; Disease Models, Animal ; Enzyme Activation/drug effects ; Humans ; Inflammation/immunology ; Interleukin-6/genetics ; Interleukin-6/metabolism* ; Janus Kinases/antagonists & inhibitors ; Janus Kinases/metabolism* ; Liver/pathology ; Liver Neoplasms/pathology* ; Morpholines/pharmacology ; Niclosamide/pharmacology ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; STAT3 Transcription Factor/antagonists & inhibitors ; STAT3 Transcription Factor/metabolism* ; Signal Transduction/drug effects ; Zebrafish ; Zebrafish Proteins/antagonists & inhibitors ; Zebrafish Proteins/metabolism*
Abstract
Chronic inflammation is an important process leading to tumorigenesis. Therefore, targeting and controlling inflammation can be a promising cancer therapy. Inflammation is often caused by a variety of inflammatory cytokine such as the interleukin (IL)-6, a pleiotrophic cytokine known to be involved in the tumorigenesis. In this study, an in vivo hepatic tumorigenesis model of zebrafish was generated to demonstrate a direct consequence of the human IL6 expression causing hepatocarcinogenesis. To do this, an elevated expression of the hIL6 gene was established to specifically target the zebrafish hepatocytes by transgenesis. Interestingly, the elevated hIL6 expression caused the chronic inflammation which results in a massive infiltration of inflammatory cells. This eventually resulted in the generation of various dysplastic lesions such as clear cell, small cell, and large cell changes, and also eosinophilic and basophilic foci of hepatocellular alteration. Hepatocellular carcinoma was then developed in the transgenic zebrafish. Molecular characterization revealed upregulation of the downstream components involved in the IL6-mediated signaling pathways, especially PI3K/Akt and JAK/STAT3 pathways. Further investigation indicated that PI3K was the most reactive to the infiltrated inflammatory cells and dysplasia with large cell change, whereas STAT3 was heavily activated in the region with dysplastic foci, suggesting that the JAK/STAT3 pathway was mainly implicated in the hepatic tumorigenesis in the current model. Our present study provides an in vivo evidence of the relationship between chronic inflammation and tumorigenesis and reinforces the pivotal role of IL6 in the inflammation-associated hepatocarcinogenesis.
Files in This Item:
T201503252.pdf Download
DOI
10.1016/j.neo.2015.07.005
Appears in Collections:
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Park, Seung Woo(박승우) ORCID logo https://orcid.org/0000-0001-8230-964X
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Leem, Ga Lam(임가람)
Jung, In Hye(정인혜)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/141021
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