title: Predominant Activation of JAK/STAT3 Pathway by Interleukin-6 Is Implicated in Hepatocarcinogenesis.
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.
authors: Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors: In Hye
authors: IH
authors: Jung
authors: Boston University College of Art and Science, Boston, MA, USA.
authors: Jeffrey Hyun-Kyu
authors: JH
authors: Choi
authors: Research Institute of SMT Bio, SMT Bio Co., Ltd. Seoul, Korea.
authors: Yong-Yoon
authors: YY
authors: Chung
authors: Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors: Ga-Lam
authors: GL
authors: Lim
authors: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
authors: Young-Nyun
authors: YN
authors: Park
authors: Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea. Electronic address: swoopark@yuhs.ac.
authors: Seung Woo
authors: SW
authors: Park
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002471:Cell Transformation, Neoplastic; D003499:Cyclic S-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D009534:Niclosamide / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D003499:Cyclic S-Oxides; D015850:Interleukin-6; D053612:Janus Kinases; D009025:Morpholines; D009534:Niclosamide; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050796:STAT3 Transcription Factor; D029961:Zebrafish Proteins; C508600:IL6 protein, human; C571178:NVP-BKM120; C494089:stat3 protein, zebrafish; C517409:stattic