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
  • 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*
(all 25)
PubMed
26297436 Full text @ Neoplasia
CTD
26297436
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
Marker Marker Type Name
apaf1GENEapoptotic peptidase activating factor 1
appaGENEamyloid beta (A4) precursor protein a
baxaGENEBCL2 associated X, apoptosis regulator a
bcl2aGENEBCL2 apoptosis regulator a
ccnd1GENEcyclin D1
cd4-1GENECD4-1 molecule
cd8aGENECD8a molecule
cishaGENEcytokine inducible SH2-containing protein a
cxcl8aGENEchemokine (C-X-C motif) ligand 8a
eif4eaGENEeukaryotic translation initiation factor 4ea
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Figures
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
yu9TgTransgenic Insertion
    yu11TgTransgenic Insertion
      yu17TgTransgenic Insertion
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        No data available
        Fish
        No data available
        Antibodies
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        EGFPEFGEGFP
        GAL4EFGGAL4
        RFPEFGRFP
        1 - 3 of 3
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        Mapping
        No data available
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        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.