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. 2024 Sep 6;24(5):1186-1198.
doi: 10.17305/bb.2024.10367.

Echinacoside ameliorates hepatic fibrosis and tumor invasion in rats with thioacetamide-induced hepatocellular carcinoma

Ajwan Z Albalawi  1 , Areej S Alatawi  1 , Shekha M Al-Atwi  1 , Lama S Alhwyty  1 , Kadi M Alharbi  1 , Shahad A Alshehri  1 , Wasayf A Almarwani  1 , Khulud K Aljohani  1 , Hanan M Hassan  2 , Mohammed M H Al-Gayyar  3
Affiliations

Echinacoside ameliorates hepatic fibrosis and tumor invasion in rats with thioacetamide-induced hepatocellular carcinoma

Ajwan Z Albalawi et al. Biomol Biomed. .

Abstract

Hepatocellular carcinoma (HCC) affects approximately 800,000 individuals globally each year. Despite advancements in HCC treatments, there is still a pressing need to identify new drugs that can combat resistance. One potential option is echinacoside, a natural caffeic acid glycoside with antioxidant, anti-inflammatory, antidepressant, and antidiabetic properties. Therefore, we aimed to investigate the ability of echinacoside to exhibit antitumor activity against HCC in rats through ameliorating hepatic fibrosis and tumor invasion. Rats were given thioacetamide to induce HCC, and some were given 30 mg/kg of echinacoside twice a week for 16 weeks. The liver impairment was assessed by measuring serum α-fetoprotein (AFP) and examining liver sections stained with Masson trichrome or anti-transforming growth factor (TGF)-β1 antibodies. The hepatic expression of mRNA and protein levels of TGF-β1, β-catenin, SMAD4, matrix metalloproteinase-9 (MMP9), phosphoinositide 3-kinases (PI3K), mammalian target of rapamycin (mTOR), connective tissue growth factor 2 (CCN2), E-Cadherin, platelets derived growth factor (PDGF)-B and fascin were also analyzed. Echinacoside improved the survival rate of rats by decreasing serum AFP and the number of hepatic nodules. Examination of micro-images indicated that echinacoside can reduce fibrosis. It also significantly decreased the expression of TGF-β1, β-catenin, SMAD4, MMP9, PI3K, mTOR, CCN2, PDGF-B, and fascin while enhancing the expression of E-Cadherin. In conclusion, echinacoside exhibits a protective effect against HCC by increasing survival rates and decreasing tumor growth. It also acts as an inhibitor of the hepatic tissue fibrosis pathway by reducing the expression of TGF-β1, β-catenin, SMAD4, PI3K, CCN2, PDGF-B and mTOR. Additionally, it prevents tumor invasion by suppressing MMP9 and fascin, and increasing the expression of E-Cadherin.

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Conflict of interest statement

Conflicts of interest: Authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
Effect of HCC and 30 mg/kg echinacoside on rats’ survival (A), the average number of nodules (B), and serum AFP (C). *Significant difference as compared with the control group at P < 0.05. #Significant difference as compared with the HCC group at P < 0.05. AFP: Alpha-fetoprotein; C: Control; HCC: Hepatocellular carcinoma.
Figure 2.
Figure 2.
Hepatic sections stained with Masson trichrome in the control group (A), control group treated with echinacoside (B), HCC (C), and HCC treated with echinacoside (D). Fibrotic area was determined in 10 fields of high field power and expressed as mean ± standard deviation (E). Yellow arrows indicates areas of fibrosis. *Significant difference as compared with the control group at P < 0.05. #Significant difference as compared with the HCC group at P < 0.05. Scale bars represent 100 µm. AFP: Alpha-fetoprotein; C: Control; HCC: Hepatocellular carcinoma.
Figure 3.
Figure 3.
Effect of HCC and 30 mg/kg echinacoside on hepatic gene expression of TGF-β (A) and its hepatic protein level (B). Hepatic sections stained with anti-TGF-β antibodies in the control group (C), control group treated with echinacoside (D), HCC group (E), and HCC treated with echinacoside (F). *Significant difference as compared with the control group at P < 0.05. #Significant difference as compared with the HCC group at P < 0.05. Scale bar 100 µm. C: Control; HCC: Hepatocellular carcinoma; TGF-β: Transforming growth factor-β.
Figure 4.
Figure 4.
Effect of HCC and 30 mg/kg echinacoside on hepatic gene expression of β-catenin (A) and SMAD4 (C) as well as protein expression of β-catenin (B) and SMAD4 (D). *Significant difference as compared with the control group at P < 0.05. #Significant difference as compared with the HCC group at P < 0.05. C: Control; HCC: Hepatocellular carcinoma.
Figure 5.
Figure 5.
Effect of HCC and 30 mg/kg echinacoside on hepatic gene expression of PI3K (A) and mTOR (C) as well as protein expression of PI3K (B) and mTOR (D). *Significant difference as compared with the control group at P < 0.05. #Significant difference as compared with the HCC group at P < 0.05. C: Control; HCC: Hepatocellular carcinoma; mTOR: Mammalian target of rapamycin; PI3K: Phosphoinositide 3-kinases.
Figure 6.
Figure 6.
Effect of HCC and 30 mg/kg echinacoside on hepatic gene expression of PDGF-B (A) and CCN2 (C) as well as protein expression of PDGF-B (B) and CCN2 (D). *Significant difference as compared with the control group at P < 0.05. #Significant difference as compared with the HCC group at P < 0.05. C: Control; HCC: Hepatocellular carcinoma; PDGF-B: Platelet-derived growth factor-B; CCN2: Cellular communication network factor 2.
Figure 7.
Figure 7.
Effect of HCC and 30 mg/kg echinacoside on hepatic gene expression of MMP9 (A) and fascin (C) as well as protein expression of MMP9 (B) and fascin (D). *Significant difference as compared with the control group at P < 0.05. #Significant difference as compared with the HCC group at P < 0.05. C: Control; HCC: Hepatocellular carcinoma; MMP9: Matrix metalloproteinase 9.
Figure 8.
Figure 8.
Effect of HCC and 30 mg/kg echinacoside on hepatic gene expression of E-Cadherin (A) and its hepatic protein level (B). Hepatic sections stained with anti-E-Cadherin antibodies in the control group (C), control group treated with echinacoside (D), HCC group (E), and HCC treated with echinacoside (F). *Significant difference as compared with the control group at P < 0.05. #Significant difference as compared with the HCC group at P < 0.05. Scale bar 100 µm. C: Control; HCC: Hepatocellular carcinoma.
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