Abstract
BackgroundActivated hepatic stellate cells (aHSCs) play an important role in the progression of hepatocellular carcinoma (HCC). Here, we determined if cytokines secreted in response to the herbal compound “Songyou Yin” (SYY) treatment of aHSCs could influence invasiveness and metastatic capabilities of hepatoma cells.MethodsPrimary rat hepatic stellate cells (HSCs) were isolated, activated, divided into SYY treated and untreated (nSYY) groups, and conditioned media (CM-SYY and CM-nSYY, respectively) were collected. The hepatoma cell line, McA-RH7777 was cultured for 4 weeks with SYY, CM-SYY, and CM-nSYY, designated McA-SYY, McA-SYYCM and McA-nSYYCM. The invasiveness and metastatic capabilities were evaluated using Matrigel invasion assay in vitro and pulmonary metastasis in vivo. Matrix metalloproteinase-2 (MMP-2), MMP-9, E-cadherin, N-cadherin, and vimentin protein levels in McA-SYYCM and McA-nSYYCM were evaluated by Western blot. Cytokine levels in conditioned media were tested using enzyme-linked immunosorbent assay (ELISA).ResultsMatrigel invasion assay indicated that the number of McA-SYYCM cells passing through the basement membrane was less than in McA-nSYYCM cells (P < 0.01). Similar results were also observed in vivo for lung metastasis. McA-SYYCM cells showed less pulmonary metastasis capabilities than McA-nSYYCM cells (P < 0.001). The reduced expression of MMP-2 and reversed epithelial to mesenchymal transition with E-cadherin upregulation, and N-cadherin and vimentin downregulation were also found in McA-SYYCM compared to McA-nSYYCM. Metastasis-promoting cytokines hepatocyte growth factor, interleukin-6, transforming growth factor-β1, and vascular endothelial growth factor were markedly decreased in CM-SYY compared to CM-nSYY.ConclusionsSYY attenuates hepatoma cell invasiveness and metastasis capabilities through downregulating cytokines secreted by activated hepatic stellate cells.
Highlights
Activated hepatic stellate cells play an important role in the progression of hepatocellular carcinoma (HCC)
We have recently reported that Songyou Yin (SYY), a mixture of five herbs inhibited HCC growth, prolonged survival by inducing tumor apoptosis associated with caspase-3 activation, and inhibited invasiveness associated with downregulation of matrix metalloproteinase-2 (MMP-2) [20]
Activated Hepatic stellate cells and the hepatoma cell line McARH7777 were treated with Songyou Yin” (SYY) 2 mg/ml for 0, 4, 8, 12 h demonstrated strange decline in release of lactate dehydrogenase (LDH) compared with the control group
Summary
Activated hepatic stellate cells (aHSCs) play an important role in the progression of hepatocellular carcinoma (HCC). The majority of HCC patients have a background of chronic liver disease that primarily develops in cirrhosis, such as chronic infection by hepatitis B virus and hepatitis C virus, alcoholic injury [2]. HCC may complicate non-alcoholic fatty liver disease (NAFLD) with mild or absent fibrosis, greatly expanding the population of HCC patients potentially at higher risk [3]. Activated hepatic stellate cells (aHSCs) have a key role in fibrogenesis and in filtrates of the HCC stroma, where they could play a critical role in HCC progression. AHSCs are recognized as central in the development and progression of hepatocellular carcinoma [4,5]. Only limited therapeutic options are currently available for this condition
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