PUBLICATION
Predominant Activation of JAK/STAT3 Pathway by Interleukin-6 Is Implicated in Hepatocarcinogenesis
- Authors
- Jung, I.H., Choi, J.H., Chung, Y.Y., Lim, G.L., Park, Y.N., Park, S.W.
- ID
- ZDB-PUB-150825-58
- Date
- 2015
- Source
- Neoplasia (New York, N.Y.) 17: 586-97 (Journal)
- Registered Authors
- Park, Seung Woo
- Keywords
- none
- MeSH Terms
-
- Disease Models, Animal
- STAT3 Transcription Factor/antagonists & inhibitors
- STAT3 Transcription Factor/metabolism*
- Liver Neoplasms/pathology*
- Interleukin-6/genetics
- Interleukin-6/metabolism*
- Zebrafish
- Morpholines/pharmacology
- Cell Transformation, Neoplastic
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/metabolism*
- Aminopyridines/pharmacology
- Enzyme Activation/drug effects
- Humans
- Janus Kinases/antagonists & inhibitors
- Janus Kinases/metabolism*
- Cyclic S-Oxides/pharmacology
- Carcinoma, Hepatocellular/pathology*
- Animals
- Liver/pathology
- Phosphatidylinositol 3-Kinases/antagonists & inhibitors
- Phosphatidylinositol 3-Kinases/metabolism
- Inflammation/immunology
- Niclosamide/pharmacology
- Signal Transduction/drug effects
- PubMed
- 26297436 Full text @ Neoplasia
- CTD
- 26297436
Citation
Jung, I.H., Choi, J.H., Chung, Y.Y., Lim, G.L., Park, Y.N., Park, S.W. (2015) Predominant Activation of JAK/STAT3 Pathway by Interleukin-6 Is Implicated in Hepatocarcinogenesis. Neoplasia (New York, N.Y.). 17:586-97.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping