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.

Hepatocellular carcinoma: Exploring the impact of ethnicity on molecular biology

“…This pathway seems to be related to chronic inflammation that could be triggered by pro-inflammatory cytokines such as IL-6 (interleukin-6). This has been shown elegantly by zebrafish model harbouring human IL-6 published by Jung et al (Jung et al, 2015). A constitutive activation of JAK/STAT (signal transducer and activator of transcription) pathway dependent on aberrant hypermethylation of SSI-1 (stress survival islet-1) gene has been identified in a significant percentage of HCC patients, both in Western (65% (Yoshikawa et al, 2001)) and in Asian populations (53% (Nagai et al, 2002)).…”

IL-17 Activates the IL-6/STAT3 Signal Pathway in the Proliferation of Hepatitis B Virus-Related Hepatocellular Carcinoma

“…Additionally, IL-6 plays an important role in promoting the phosphorylation of both STAT3 and Jak2 [42]. Activation of the STAT3 by phosphorylation in response to IL6 turns on the transcriptions of many downstream genes involved in normal hepatic development [43]. The IL-6-induced STAT3 signaling pathway in tumor cells enhances proliferation, proangiogenic, and antiapoptotic genes.…”

Anti-proliferative and apoptotic effects of quinine in human Hep-2 laryngeal cancer and KB oral cancer cell

“…Inhibition of inflammatory mediators are targeted to develop an effective strategy to prevent inflammatory diseases (Jung et al, 2015;Liu et al, 2014). The over expression of iNOS, COX-2 and IL-6 has been previously reported in head and neck squamous cell carcinoma as well as in many cancers to promote the inflammatory response (Jabłonska et al, 2006;Van Tubergen et al, 2011;Mohammad et al, 2011).…”