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

Life Sci. 2017 Sep 15:185:114-125. doi: 10.1016/j.lfs.2017.07.026. Epub 2017 Jul 25.


Aims: Wnt3a and Wnt5a are ligands orchestrating the canonical and non-canonical pathways, respectively, with 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, 150mg/kg/day), HCC (receiving TAA, 200mg/kg twice weekly for 14weeks) and HP-HCC (receiving HP and TAA). Gene expressions of Wnt3a, Wnt5a, β-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 (10ng/ml) in presence or absence of HP (100μM) was performed.

Key findings: HCC group exhibited a significant increase in Wnt3a, β-catenin, Cyclin D1 and Wnt5a gene expressions, as well as, their protein levels. HP significantly prevented TAA-activated Wnt3a/β-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/β-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.

Keywords: Hepatocellular carcinoma; Hesperidin; Thioacetamide; Wnt3a; Wnt5a; β-catenin.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / prevention & control*
  • Gene Expression Regulation / drug effects
  • Hesperidin / pharmacology*
  • Liver Neoplasms / prevention & control*
  • Male
  • Oxidative Stress / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Thioacetamide / toxicity
  • Wnt Signaling Pathway / drug effects*
  • Wnt-5a Protein / metabolism
  • Wnt3A Protein / metabolism


  • Wnt-5a Protein
  • Wnt3A Protein
  • Thioacetamide
  • Hesperidin