Modulation of miR-192/NF-κB/ TGF-β/ E-cadherin by thymoquinone protects against diethylnitrosamine /carbon tetrachloride hepatotoxicity

Ashour, Hend and Farghaly, Maha Eid and Khowailed, Akef Abdelhalim and Aboulhoda, Basma Emad and Rashed, Laila Ahmed and Elsebaie, Mohamed Mahmoud and Gaber, Safy Salah (2022) Modulation of miR-192/NF-κB/ TGF-β/ E-cadherin by thymoquinone protects against diethylnitrosamine /carbon tetrachloride hepatotoxicity. Physiology International, 109 (3). pp. 371-387. ISSN 2498-602X

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Abstract

Scientific efforts have been made for a better understanding of the pathogenesis of hepatocellular carcinoma (HCC). We investigated the possible role of miR-192/nuclear factor-κB (NF-κB)/transforming growth factor-β (TGF-β)/E-cadherin in hepatic tumorigenesis. We expected a modulatory impact of thymoquinone. Thirty adult male rats were assigned into 3 groups ( n = 10); (1) Control group. Group (2): Experimental HCC induced by intraperitoneal injection of diethylnitrosamine (DENA) followed by carbon tetrachloride (CCl4). Group (3): Thymoquinone 20 mg kg −1 /oral supplementation starting from the model induction to the end of the 8th week. The HCC (DENA-CCL4) model was confirmed by elevated serum levels of alpha-fetoprotein and transaminases (ALT, AST) and by histopathological examination which denoted marked cellular atypia and features of neoplasia. Suppressed hepatic miR-192 and E-cadherin expression were detected in the HCC (DENA-CCL4) group accompanied by elevated tumor necrosis factor (TNF-α), interleukin (IL6)/NF-κB & TGF-β1. Thymoquinone treatment protected the rat livers from hepatic tumorigenesis. Thymoquinone diminished ( P < 0.001) alpha-fetoprotein and improved ALT, AST. It preserved hepatic miR-192 and normal E-cadherin expression. Thymoquinone-treated rats showed abrogated TNF-α, IL6/NF-κB/TGF-β. Thymoquinone increased cell apoptosis markers Bax/Bcl2 and diminished cellular atypia. Pearson's correlations revealed positive association between miR-192 expression and E-cadherin and Bax/Bcl2 as well, and it was negatively correlated to alpha-fetoprotein, NF-κB and TGF-β and the cellular atypia score. In conclusion, thymoquinone protected the liver tissues through preserving miR-192 and E-cadherin and aborting NF-κB & TGF-β signaling. The current results highlight a new role for thymoquinone in preventing hepatic tumorigenesis.

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