The herbal compound Songyou Yin (SYY) inhibits hepatocellular carcinoma growth and improves survival in models of chronic fibrosis via paracrine inhibition of activated hepatic stellate cells
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Yang Bu1,2,*, Qing-An Jia3,*, Zheng-Gang Ren2,*, Tong-Chun Xue2, Quan-Bao Zhang2, Ke-Zhi Zhang2, Qiang-Bo Zhang2, Yang You2, Hui Tian2, Lun-Xiu Qin3, Zhao-You Tang2
1Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750001, China
2Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
3Cancer Center, Institutes of Biomedical Sciences, General Surgery, Huashan Hospital, Fudan University, Shanghai 200032, China
*These authors have contributed equally to this work
Zhao-You Tang, e-mail: email@example.com
Keywords: Songyou Yin, hepatocellular carcinoma, chronic fibrosis, activated hepatic stellate cells
Received: April 08, 2014 Accepted: October 09, 2015 Published: October 22, 2015
Chronic fibrosis is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathological progression of hepatic fibrosis has been linked to cellular processes that promote tumor growth and metastasis. Several recent studies have highlighted the cross-talk between tumor cells and activated hepatic stellate cells (aHSCs) in HCC. The herbal compound Songyou Yin (SYY) is known to attenuate hepatoma cell invasion and metastasis via down-regulation of cytokine secretion by aHSCs. However the underlying mechanism of SYY treatment in reversal of hepatic fibrosis and metastasis of liver cancers is not known. In the current study, a nude mouse model with liver fibrosis bearing orthotopic xenograft was established and we found that SYY could reduce associated fibrosis, inhibit tumor growth and improve survival. In the subcutaneous tumor model with fibrosis, we found that SYY could inhibit liver cancer. In vitro, hepatoma cells incubated with conditioned media (CM) from SYY treated aHSCs showed reduced proliferation, decrease in colony formation and invasive potential. SYY treated group showed altered gene expression, with 1205 genes up-regulated and 1323 genes down-regulated. Gene cluster analysis indicated that phosphatidylinositol-3-kinase (PI3K) was one of the key genes altered in the expression profiles. PI3K related markers were all significantly down-regulated. ELISA also indicated decreased secretion of cytokines which were regulated by PI3K/AKT signaling after SYY treatment in the hepatic stellate cell line, LX2. These data clearly demonstrate that SYY therapy inhibits HCC invasive and metastatic potential and improves survival in nude mice models with chronic fibrosis background via inhibition of cytokine secretion by activated hepatic stellate cells.
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