Hepatic Premalignant Alterations Triggered by Human Nephrotoxin Aristolochic Acid I in Canines

摘要

Aristolochic acid I (AM) existing in plant drugs from Aristolochia species is an environmental human carcinogen associated with urothelial cancer. Although gene association network analysis demonstrated gene expression profile changes in the liver of human T253 knock-in mice after acute AAI exposure, to date, whether AM causes hepatic tumorigenesis is still not confirmed. Here, we show that hepatic premalignant alterations appeared in canines after a 10 -day AAI oral administration (3 mg/kg/day). We observed c-Myc oncoprotein and oncofeta] RNA-binding protein Lin28B overexpressions accompanied by cancer progenitor-like cell formation in the liver by AM exposure, Meanwhile, we found that forkhead box 01 (FOXO1) was robustly phosphorylated, thereby shuttling into the cytoplasm of hepatocytes. Furthermore, utilizing microarray and qRT-PCR analysis, we confirmed that microRNA expression significantly dysregulated hi the liver treated with AAI. Among them, we particularly focused on the members in let-7 miRNAs and rniR23a clusters, the downstream of c-Myc and 1L6 receptor (IL6R,611) signaling pathway linking the premalignant alteration. Strikingly, when IL6 was added in vitro, 11,614,/111NF-kappa B signaling activation contributed to the increase of FOXO1 phosphorylalion by the let -7b inhibitor. Therefore, it highlights the new insight into the interplay of the network in hepatic turnorigenesis by AA1 exposure, and also suggests that anti-premalignant therapy may be crucial for preventing AAI-induced hepatocarcinogenesis. Cancer Prev Res (C) 2016 AACR