Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model

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• 作者：Sook In Chung¹ ; Hyuk Moon¹ ; Hye-Lim Ju² ; Kyung Joo Cho¹ ; Do Young Kim³ ; Kwang-Hyub Han³ ; Jung Woo Eun⁴ ; Suk Woo Nam⁴ ; Silvia Ribback⁵ ; Frank Dombrowski⁵ ; Diego F. Calvisi⁵ ; Simon Weonsang Ro¹ ; ² ; ^{simonr@yuhs.ac" class="auth_mail" title="E-mail the corresponding author}
• 关键词：α-SMA ; α-smooth muscle actin ; ALP ; alkaline phosphatase ; ALT ; alanine aminotransferase ; AST ; aspartate aminotransferase ; ECM ; extracellular matrix ; EMT ; epithelial-to-mesenchymal transition ; EGFP ; enhanced green fluorescent protein ; Gli ; glioblastoma ; HCA ; hepatocellular adenoma ; HCC ; hepatocellular carcinoma ; HHIP ; Hedgehog interacting protein ; HSC ; hepatic stellate cell ; IHC ; immunohistochemistry ; IL ; interleukin ; MMP ; matrix-degrading metalloproteinase ; mRNA ; messenger RNA ; NAFLD ; non-alcohol
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：64
• 期：3
• 页码：618-627
• 全文大小：5164 K

文摘

Liver fibrosis is an increasing health concern worldwide and a major risk factor for hepatocellular carcinoma (HCC). Although the involvement of Hedgehog signaling in hepatic fibrosis has been known for some time, the causative role of activated Hedgehog signaling in liver fibrosis has not been verified in vivo.

Methods

Using hydrodynamics-based transfection, a transgenic mouse model has been developed that expresses Sonic Hedgehog (SHH), a ligand for Hedgehog signaling, in the liver. Levels of hepatic fibrosis and fibrosis-related gene expression were assessed in the model. Hepatic expression of SHH was induced in a murine model for hepatocellular adenoma (HCA) and tumor development was subsequently investigated.

Results

The transgenic mice revealed SHH expression in 2–5% of hepatocytes. Secreted SHH activated Hedgehog signaling in numerous cells of various types in the tissues. Hepatic expression of SHH led to fibrosis, activation of hepatic stellate cells, and an upregulation of various fibrogenic genes. Liver injury and hepatocyte apoptosis were observed in SHH mice. Persistent expression of SHH for up to 13 months failed to induce tumors in the liver; however, it promoted liver tumor development induced by other oncogenes. By employing a HCA model induced by P53^R172H and KRAS^G12D, we found that the SHH expression promoted the transition from HCA to HCC.

Conclusions

SHH expression in the liver induces liver fibrosis with concurrent activation of hepatic stellate cells and fibrogenic genes. It can also enhance hepatocarcinogenesis induced by other oncogenes.