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Hepatic Premalignant Alterations Triggered by Human Nephrotoxin Aristolochic Acid I in Canines
Ke Jin1, Kun-kai Su2, Tong Li1
1Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
Abstract:
Aristolochic acid I (AAI) 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 TP53 knock-in mice after acute AAI exposure, to date, whether AAI 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 oncofetal RNA-binding protein Lin28B overexpressions accompanied by cancer progenitor-like cell formation in the liver by AAI exposure. Meanwhile, we found that forkhead box O1 (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 in the liver treated with AAI. Among them, we particularly focused on the members in let-7 miRNAs and miR-23a clusters, the downstream of c-Myc and IL6 receptor (IL6R) signaling pathway linking the premalignant alteration. Strikingly, when IL6 was added in vitro, IL6R/NF-κB signaling activation contributed to the increase of FOXO1 phosphorylation by the let-7b inhibitor. Therefore, it highlights the new insight into the interplay of the network in hepatic tumorigenesis by AAI exposure, and also suggests that anti-premalignant therapy may be crucial for preventing AAI-induced hepatocarcinogenesis.
Insights
Aristolochic acid I (AAI) exposure causes liver premalignant changes in canines, including c-Myc and Lin28B overexpression. This study reveals molecular pathways involved in AAI-induced hepatic tumorigenesis.
Area of Science:
- Hepatology
- Toxicology
- Carcinogenesis
Background:
- Aristolochic acid I (AAI) is an environmental carcinogen linked to urothelial cancer.
- Previous studies suggested AAI affects gene expression in mouse livers, but its role in hepatic tumorigenesis remained unconfirmed.
Purpose of the Study:
- To investigate whether Aristolochic acid I (AAI) induces hepatic tumorigenesis.
- To elucidate the molecular mechanisms underlying AAI-induced liver alterations.
Main Methods:
- Oral administration of AAI to canines for 10 days.
- Analysis of c-Myc, Lin28B, and FOXO1 expression and localization.
- Microarray and qRT-PCR for microRNA expression profiling.
- In vitro experiments involving IL6 stimulation and let-7b inhibitor.
Main Results:
- Hepatic premalignant alterations, including c-Myc and Lin28B overexpression and cancer progenitor-like cell formation, were observed in canines after AAI exposure.
- AAI exposure led to robust phosphorylation and cytoplasmic translocation of FOXO1.
- Significant microRNA dysregulation was confirmed, with a focus on let-7 miRNAs and miR-23a clusters.
- In vitro studies showed IL6R/NF-κB signaling activation contributes to FOXO1 phosphorylation via let-7b inhibition.
Conclusions:
- AAI exposure induces hepatic premalignant alterations and dysregulates key molecular pathways, including c-Myc, Lin28B, FOXO1, and microRNAs.
- The findings highlight a novel interplay of molecular networks in AAI-induced hepatic tumorigenesis.
- Anti-premalignant therapy may be essential for preventing AAI-induced liver cancer.
