cDNA microarray profiling of rat cholangiocarcinoma induced by thioacetamide

Abstract

Abstract. Cholangiocarcinoma (CCA) is a malignant neoplasm affecting thousands of individuals worldwide. CCA develops through a multistep process. In the current study, an oral thioacetamide (TAA)-induced model of rat CCA was established which generates the histological progression of human CCA, particularly the mass-forming type. Seven male Sprague-Dawley rats were treated with TAA for 24 weeks to induce CCA. Following the generation of the rat CCA model, whole rat genomic oligo microarray was performed to examine gene expression profiles in CCA and non-cancerous liver samples. In brief, 10,427 genes were found to be differentially expressed (8,318 upregulated and 3,489 downregulated) in CCA compared with non-tumor liver tissue. The top 50 genes (upregulated or downregulated) were selected and their functional involvement in various pathways associated with cancer progression was analyzed, including cell proliferation, apoptosis, metabolism and the cell cycle. In addition, increased expression of CLCA3, COL1A2, DCN, GLIPr2 and NID1, and decreased expression of CYP2C7 and SLC10A1 were validated by quantitative real-time PCR. Immunohistochemical analysis was performed to determine the protein expression levels of GLIPr2 and SLC10A1. The gene expression profiling performed in this study provides a unique opportunity for understanding the carcinogenesis of TAA-induced CAA. In addition, expression profiling of a number of specific genes is likely to provide important novel biomarkers for the diagnosis of CCA and the development of novel therapeutic strategies for CCA.

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

“…These inflammatory macrophages express WNT7B ligand in line with what has been described in other contexts (9)(10)(11). In xenografts of human CC cells, a transgenic murine line that develops CC (12), and also a well-validated, chemically induced rat model of CC (13)(14)(15)(16)(17) that reflects the progression of CC in humans, we find that depletion of macrophages or inhibition of the canonical WNT pathway results in reduced tumor burden. This strategy offers, for the first time to our knowledge, a small molecule approach to the treatment of CC in vivo.…”

“…To appropriately model CC development on the background of chronic damage, inflammation and repair, as seen in human disease, we used a model of chemically induced CC using thioacetamide (TAA). TAA induces chronic damage and regeneration, culminating in CC development after 26 weeks in both mouse and rat (Figure 2A, schematic, and Supplemental Figure 2B) that histologically and transcriptionally resembles that of the human cancer (13,15,16).…”

Overexpression of PDZK1IP1, EEF1A2 and RPL41 genes in intrahepatic cholangiocarcinoma

“…Thus tumorigenesis and progression of iCCA may lead to the dysfunction of liver metabolism. Consistent with the present results, the expression of the SLC10A1 gene (a member of the sodium/bile acid cotransporter family which participates in the enterohepatic circulation of bile acids) was decreased in cholangiocarcinoma (26). SULT2A1, encoding a protein which catalyzes the sulfation of steroids and bile acids in the liver and adrenal glands, and the ABCG8 gene, which is associated with cholesterol absorption, were downregulated in iCCA.…”

Molecular Changes Following Induction of Hepatocellular Carcinoma by Diethylnitrosamine and Thioacetamide, and Subsequent Treatment with Dioscorea membranacea Extract

“…Such a sex difference is also found in human HCC [41]. The effect on the "coagulation" pathway appears to correspond with TAA-related thrombocytopenia [53], while the "apical_junction" and "apical_surface pathways appear to reflect TAA-induced bile duct epithelial damage [54,55]. The pro-fibrotic effects of TAA are well-studied and seem to be a sequel of its cytotoxicity which peaks between 24 and 48 hours after administration [44,47].…”