Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?

Abstract

Hepatocellular carcinoma (HCC) is one of the most fatal and fastest-growing cancers. Recently, non-alcoholic steatohepatitis (NASH) has been recognized as a major HCC catalyst. However, it is difficult to decipher the molecular mechanisms underlying the pathogenesis of NASH and understand how it progresses to HCC by studying humans. Progress in this field depends on the availability of reliable preclinical models amenable to genetic and functional analyses and exhibiting robust NASH-to-HCC progression. Although numerous mouse models of NASH have been described, many do not faithfully mimic the human disease and few reliably progress to HCC. Here, we review current literature on the molecular etiology of NASH-related HCC and critically evaluate existing mouse models and their suitability for studying this malignancy. We also compare human transcriptomic and histopathological profiles with data from MUP-uPA mice, a reliable model of NASH-driven HCC that has been useful for evaluation of HCC-targeting immunotherapies.

Keywords: RNA-seq; fatty liver; hepatocellular carcinoma; mouse models; non-alcoholic steatohepatitis; obesity.

Figure 1.. Histological and transcriptomic alignment between the MUP-uPA mouse model and human NASH.

(A) Histological comparison of MUP-uPA mice and human NASH; data previously published (Nakagawa et al., 2014). (B) RNA-Seq data from human NASH patients and normal individuals (left) and MUP-uPA mice fed either HFD or normal chow (right). All terms are enriched with a p < 0.05, the color coding represents the p-value for enrichments calculated for the MUP-uPA+HFD mice, the darker red the more significant, and the size of the nodes represents the p-value for enrichments calculated for the human data (all nodes that are only enriched for the human data are light red, all nodes that are only enriched for MUP-uPA are small). (C) Gene alignment between our current data set of NASH patients (n = 3) compared with four other publicly available data sets.