Chronically high level of  tgfb1a  induction causes both hepatocellular carcinoma and cholangiocarcinoma via a dominant Erk pathway in zebrafish

Chuan Yan; Qiqi Yang; Han-Ming Shen; Jan M. Spitsbergen; Zhiyuan Gong

doi:10.18632/oncotarget.20357

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Chronically high level of tgfb1a induction causes both hepatocellular carcinoma and cholangiocarcinoma via a dominant Erk pathway in zebrafish

Chuan Yan, Qiqi Yang, Han-Ming Shen, Jan M. Spitsbergen and Zhiyuan Gong _

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Oncotarget. 2017; 8:77096-77109. https://doi.org/10.18632/oncotarget.20357

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Abstract

Chuan Yan1,2, Qiqi Yang1, Han-Ming Shen3, Jan M. Spitsbergen4 and Zhiyuan Gong1,2

1Department of Biological Sciences, National University of Singapore, Singapore

2National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore

3Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

4Department of Microbiology, Oregon State University, Corvallis, OR, USA

Correspondence to:

Zhiyuan Gong, email: [email protected]

Keywords: TGFb, hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), non-alcoholic steatohepatitis (NASH), leptin

Received: May 17, 2017 Accepted: June 30, 2017 Published: August 18, 2017

ABSTRACT

Liver cancers including both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) have increased steadily with the prevalence of non-alcoholic steatohepatitis (NASH), but the underlying mechanism for the transition from NASH to liver cancers remains unclear. Here we first employed diet-induced NASH zebrafish and found that elevated level of satiety hormone, leptin, induced overexpression of tgfb1. Then we developed tgfb1a transgenic zebrafish for inducible, hepatocyte-specific expression. Interestingly, chronically high tgfb1a induction in hepatocytes could concurrently drive both HCC and CCA. Molecularly, oncogenicity of Tgfb1 in HCC was dependent on the switch of dominant activated signaling pathway from Smad to Erk in hepatocytes while concurrent activation of both Smad and Erk pathways in cholangiocytes was essential for Tgfb1-induced CCA. These findings pinpointed the novel role of Tgfb1 as a central regulator in the two major types of liver cancers, which was also supported by human liver disease samples.

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Chronically high level of tgfb1a induction causes both hepatocellular carcinoma and cholangiocarcinoma via a dominant Erk pathway in zebrafish

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