Mechanistic insights into Thorium-232 induced liver carcinogenesis: The driving role of Wnt/-catenin signaling pathway

Thorium-232 (Th-232), a naturally-occurring radioactive element with high potential of nuclear fuel is now being utilized in advanced nuclear reactors for CO2-free energy generation. To achieve all-round capability in Th-fuel cycle for health and environment, understanding the biological effects of Th-232 at cellular and molecular level are extremely important. The present study investigated long-term effects (6 and 12 months) of Th-232 (4, 10 and 20 mg/kg) on gene expression in mice liver (major target organ). Analysis of differentially expressed genes (DEGs, >= 2.0 folds, p < 0.05) showed that with the increase of Th dose (4 to 20 mg/kg), the number of upregulated DEGs increased and the number of downregulated DEGs decreased significantly. A significant number of upregulated DEGs (10 genes in 6 months and 14 genes in 12 months) were found common between 4 and 20 mg/kg. Gene Ontology analysis revealed significant (P-adj similar to 10(-6)-10(-28)) enrichment of upregulated DEGs for metabolic process, signal transduction, cell death, cell cycle and cell proliferation. KEGG pathway analysis showed DEGs significantly enriched in several cancer-related pathways including hepatocellular carcinoma (HCC). Protein-protein interaction analysis further revealed statistically significant functional interaction (p-value similar to 10-6-10-10) among the proteins of HCC, which identified beta-catenin as one of the most significant signaling nodes in association with myc, an oncogene and p53, a tumor suppressor. Importantly, these results were corroborated by quantitative real time-polymerase chain reaction and western blotting in liver tissues of animals exposed to Th-232. This study insights Wnt/beta-catenin signaling network attributable to drive Th-induced liver carcinogenesis, which may have significant implications for management of long-term effects of Th-232.