Therapeutic effects of blocking β-catenin against hepatocellular carcinoma-induced activation of inflammation, fibrosis and tumor invasion

• Published in: Biomedicine & pharmacotherapy Vol. 135; p. 111216
• Main Authors: Hassan, Hanan M., El-Kannishy, Sherif M H, Alattar, Abdullah, Alshaman, Reem, Hamdan, Ahmed M, Al-Gayyar, Mohammed M H
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.03.2021; Elsevier
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Antineoplastic Agents - pharmacology; beta Catenin - antagonists & inhibitors; beta Catenin - metabolism; Cell Movement - drug effects; Cytokines - genetics; Cytokines - metabolism; Fibroblast growth factor (FGF)-2; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; Fibrosis; iCRT14; Inflammation Mediators - metabolism; integrin-β6; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - drug therapy; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; Male; Matrix metalloproteinase (MMP)9; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Neoplasm Invasiveness; Neovascularization, Pathologic; Pyridines - pharmacology; Pyrroles - pharmacology; Rats; Rats, Sprague-Dawley; Thiazolidinediones - pharmacology; Thioacetamide; Transforming growth factor (TGF)-β1; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Wnt Signaling Pathway; β-catenin; Transforming growth factor (TGF)-β1; NFκB; IHC; IP; HCC; Fibroblast growth factor (FGF)-2; AFP; IL-1β; FGF-2; β-catenin; integrin-β6; TNF-α; ANOVA; RT-PCR; TGF-β1; SPSS; LPA; iCRT14; GAPDH; MMP-9; ELISA; Matrix metalloproteinase (MMP)9
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.111216

[Display omitted] •iCRT14 is a β-catenin blocker.•iCRT14 significantly increased the survival of HCC rats.•iCRT14 treatment exhibited antitumor effects against HCC.•iCRT14 suppressed liver tissue inflammation, fibrosis and angiogenesis. Destructive effects of hepatocellular carcinoma (HCC) is enhanced by many cellular mechanisms including activation of fibrosis, inflammation and tumor invasion. Therefore, this study was conducted to investigate the therapeutic effects of iCRT14, β-catenin blocker, on HCC. In addition, the molecular effects of iCRT14 will be investigated on inflammation, fibrosis and tumor invasion pathways. After inducting HCC in rats, hepatic tissues were used for determination of the expression of β-catenin, nuclear factor (NF)κB, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, matrix metalloproteinase (MMP)9, transforming growth factor (TGF)-β1, fibroblast growth factor (FGF)-2 and integrin-β6. Hepatic tissues were stained with hematoxylin/eosin and with anti-Ki67. Results revealed that iCRT14 significantly increased the survival percent of HCC rats, reduced both α-fetoprotein and average number of nodules. In parallel, hepatic sections from HCC rats stained with hematoxylin/eosin revealed vacuolated cytoplasm and necrotic nodules, which were attenuated by treatment with iCRT14. Finally, treating HCC rats with iCRT14 resulted in reduction of the expression of NFκB, TNF-α, IL-1β, TGF-β1, MMP9, FGF-2 and integrin-β6. In conclusion, iCRT14 treatment exhibited antitumor effects against HCC through impairing β-catenin signaling pathway. iCRT14 suppressed liver tissue inflammation, fibrosis and angiogenesis, possibly via reducing expression of NFκB, TNF-α, IL-1β, TGF-β1, MMP-9, FGF-2.