Exacerbation of Liver Tumor Metastasis in twist1a+/xmrk+ Double Transgenic Zebrafish following Lipopolysaccharide or Dextran Sulphate Sodium Exposure.

Jeng-Wei Lu,Liang-In Lin,Dong Liu,Zhiyuan Gong,Yuxi Sun

doi:10.3390/ph14090867

Abstract

The poor prognosis for patients with hepatocellular carcinoma (HCC) is related directly to metastasis. The Twist1 gene encodes for a transcription factor essential to embryogenesis. It has also been shown to promote epithelial-to-mesenchymal transition (EMT), invasion, and metastasis; however, there is currently no in vivo evidence that Twist1 plays a role in the metastasis of liver tumors. Zebrafish are increasingly being used as an alternative cancer model. In the current study, an adult-stage zebrafish HCC model was used to examine the synergistic effects of twist1a and xmrk, a well characterized oncogene, during HCC metastasis. We also examined the effects of two inflammatory agents, lipopolysaccharides (LPS) and dextran sulfate sodium (DSS), on the hepatocyte-specific expression of transgenic twist1a and xmrk. The conditional overexpression of twist1a and xmrk was shown to promote liver tumor metastasis in zebrafish, resulting in increased apoptosis and cell proliferation as well as tumor maintenance and propagation independent of the inherent EMT-inducing activity of xmrk. Exposing twist1a+/xmrk+ transgenic zebrafish to LPS or DSS was shown to promote metastasis, indicating that the overexpression of twist1a and xmrk led to crosstalk between the signaling pathways involved in EMT. This study provides important evidence pertaining to the largely overlooked effects of signaling crosstalk between twist1a and xmrk in regulating HCC metastasis. Our results also suggest that the co-expression of twist1a/xmrk in conjunction with exposure to LPS or DSS enhances HCC metastasis, and provides a valuable in vivo platform by which to investigate tumor initiation and metastasis in the study of liver cancer.

Highlights

Hepatocellular carcinoma (HCC) is a common cause of death worldwide, in Sub-Saharan Africa and Southeast Asia [1]
Phenotype of Liver Tumor Metastasis Induced through the Weak Induction of twist1a and xmrk in Transgenic Zebrafish
The number of proliferating cells was 27% higher in the twist1a+/xmrk+ transgenic zebrafish (Figure 4B,D); the difference was less pronounced in the xmrk+ transgenic zebrafish (Figure 4D)

Summary

Introduction

Hepatocellular carcinoma (HCC) is a common cause of death worldwide, in Sub-Saharan Africa and Southeast Asia [1]. Surgical resection and liver transplantation can achieve favorable treatment outcomes for patients with nonmetastatic HCC. These patients are candidates for palliative local treatments, such as chemoembolization, radiofrequency ablation, and stereotactic radiotherapy [4]. For patients with advanced or metastatic HCC, palliative systemic therapy is the only option, and the survival benefits are limited [5]. HCC remains among the most deadly cancers, with a 5-year survival rate of only 5% [6]

Methods

Results

Conclusion