Dept. of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Dept. of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Life Sci. 2017 Sep 15;185:114-125. doi: 10.1016/j.lfs.2017.07.026. Epub 2017 Jul 25.
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.
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.
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.
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.
Wnt3a 和 Wnt5a 分别是经典和非经典途径的配体，参与肝细胞癌（HCC）的发生。橙皮苷（HP）是一种存在于柑橘类水果中的天然产物，具有抗肿瘤活性。本研究旨在探讨 HP 对硫代乙酰胺（TAA）诱导的 HCC 的潜在肝保护作用，重点研究其对 Wnt3a 和 Wnt5a 信号通路的潜在作用。
40 只大鼠等分为正常对照组、HP 对照组（给予 HP，150mg/kg/天）、HCC 组（给予 TAA，200mg/kg 每周两次，共 14 周）和 HP-HCC 组（给予 HP 和 TAA）。采用 qPCR 检测 Wnt3a、Wnt5a、β-连环蛋白和 Cyclin D1 的基因表达，采用 ELISA 和免疫组化法检测其蛋白水平及活性 caspase-3 水平。测定肝功能、氧化应激参数和髓过氧化物酶活性。在存在或不存在 HP（100μM）的情况下，用重组 Wnt3a（10ng/ml）处理 hepG2 细胞，进行 MTT 测定。
HCC 组 Wnt3a、β-连环蛋白、Cyclin D1 和 Wnt5a 的基因表达及其蛋白水平显著升高。HP 能显著阻止 TAA 激活的 Wnt3a/β-连环蛋白和 Wnt5a 通路。此外，HP 通过显著改善氧化失衡、炎症和肝功能参数、血清 ALT、AST 活性和白蛋白水平，发挥肝保护作用。
本研究首次报道了 Wnt3a/β-连环蛋白和 Wnt5a 通路在 TAA 诱导的大鼠早期 HCC 模型中的可能作用。HP 通过抑制经典和非经典 Wnt 途径的诱导，对肝癌发生具有预防作用。
