Hepatoprotective effect of hesperidin in hepatocellular carcinoma: Involvement of Wnt signaling pathways

Aims: Wnt3a and Wnt5a are ligands orchestrating the canonical and non-canonical pathways, respectively, with Wnt3a involvement in hepatocellular carcinoma (HCC). Hesperidin (HP) is a natural product found in citrus fruits and reputed for its antitumor activity. The present study aims to investigate the potential hepatoprotective effect of HP against thioacetamide (TAA)-induced HCC focusing on its potential role on Wnt3a and Wnt5a signaling pathways. Main methods: Forty rats were equally divided into groups; normal control, HP control (receiving HP, 150 mg/kg/day), HCC (receiving TAA, 200 mg/kg twice weekly for 14 weeks) and HP-HCC (receiving HP and TAA). Gene expressions of Wnt3a, Wnt5a, beta-catenin and Cyclin D1 were assessed by qPCR, while their protein levels, along with active caspase-3 level, were quantified by ELISA and immunohistochemistry. Liver functions, oxidative stress parameters and myeloperoxidase activity were measured. MTT assay of hepG2 cells treated with recombinant Wnt3a (10 ng/ml) in presence or absence of HP (100 mu M) was performed. Key findings: HCC group exhibited a significant increase in Wnt3a, beta-catenin, Cyclin D1 and Wnt5a gene expressions, as well as, their protein levels. HP significantly prevented TAA-activated Wnt3a/beta-catenin and Wnt5a pathways. Moreover, HP exerted hepatoprotective effect by significantly improving the oxidative imbalance, inflammation and liver function parameters, serum ALT, AST activities, and albumin level. Significance: Our study is the first to report the possible role of Wnt3a/beta-catenin and Wnt5a pathways in TAA-induced early HCC model in rats. HP has a prophylactic effect against hepatocarcinogenesis via preventing the induction of both canonical and non-canonical Wnt pathways.