Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis

Abstract

Toxic industrial chemicals induce liver injury, which is difficult to diagnose without invasive procedures. Identifying indicators of end organ injury can complement exposure-based assays and improve predictive power. A multiplexed approach was used to experimentally evaluate a panel of 67 genes predicted to be associated with the fibrosis pathology by computationally mining DrugMatrix, a publicly available repository of gene microarray data. Five-day oral gavage studies in male Sprague Dawley rats dosed with varying concentrations of 3 fibrogenic compounds (allyl alcohol, carbon tetrachloride, and 4,4'-methylenedianiline) and 2 nonfibrogenic compounds (bromobenzene and dexamethasone) were conducted. Fibrosis was definitively diagnosed by histopathology. The 67-plex gene panel accurately diagnosed fibrosis in both microarray and multiplexed-gene expression assays. Necrosis and inflammatory infiltration were comorbid with fibrosis. ANOVA with contrasts identified that 51 of the 67 predicted genes were significantly associated with the fibrosis phenotype, with 24 of these specific to fibrosis alone. The protein product of the gene most strongly correlated with the fibrosis phenotype PCOLCE (Procollagen C-Endopeptidase Enhancer) was dose-dependently elevated in plasma from animals administered fibrogenic chemicals (P < .05). Semiquantitative global mass spectrometry analysis of the plasma identified an additional 5 protein products of the gene panel which increased after fibrogenic toxicant administration: fibronectin, ceruloplasmin, vitronectin, insulin-like growth factor binding protein, and α2-macroglobulin. These results support the data mining approach for identifying gene and/or protein panels for assessing liver injury and may suggest bridging biomarkers for molecular mediators linked to histopathology.

Procollagen C-proteinase enhancer 1 (PCPE-1) functions as an anti-angiogenic factor and enhances epithelial recovery in injured cornea

“…Consistent with a role in collagen biosynthetic maturation, increased PCPE-1 expression is reported to accompany fibrosis onset in animal models of hepatic cirrhosis (Hassoun, et al, 2016, Ippolito, et al, 2016, Ogata, et al, 1997), cardiac fibrosis (Kessler-Icekson, et al, 2006, Yu, et al, 2013), and skeletal muscle fibrosis (Hassoun, et al, 2016); and in human dermal scarring (Wong, et al, 2014). Differences in PCPE-1 expression levels in quiescent versus proliferating smooth muscle cells (Kanaki, et al, 2000), and the induced anchorage-independent growth of cultured fibroblasts in which the PCPE-1 gene has been disrupted (Masuda, et al, 1998), have also suggested a possible role for PCPE-1 in cell proliferation control.…”

DAPK1 as an independent prognostic marker in liver cancer

“…SLC16A3, encoding a monocarboxylate transporter 4 protein, has been shown to be a downstream factor of TSTA3 immune response-mediated metabolism coupling cell cycle to postreplication repair in no-tumor hepatitis/cirrhotic tissues (Wang et al, 2012). PCOLCE (Procollagen C-Endopeptidase Enhancer) has been shown to be the strongest in its correlation with the liver fibrosis phenotype (Ippolito et al, 2016). ZBTB16, also named as PLZF, has previously been shown to be down-regulated in hepatocellular carcinoma, which supports our current study that ZBTB16 was down-regulated in liver cancer specimens compared to non-tumor liver specimens (Hui et al, 2015).…”

In vitro to in vivo extrapolation for drug-induced liver injury using a pair ranking method

“…Efforts have been made to investigate the potential of TGx data to supply better information for toxicity assessment than traditional animal toxicology studies (Liu et al, 2011(Liu et al, , 2016Ippolito et al, 2016;Sutherland et al, 2016). Furthermore, TGx has been used to investigate similarities between in vitro and in vivo assay systems and to develop translational biomarkers across the species.…”