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

Abstract

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.

WITHDRAWN: Hepatic stellate cells transmigration and remodeling are related to CCN3 in oxaliplatin-resistant hepatocellular carcinoma

“…Chen [20,21] et al has shown that prostate cancer-derived CCN3 can induce M2 macrophage infiltration, relating to the construction of the prospective environment conducive to prostate cancer metastasis. Previously, we had reported that HSCs could interact with hepatoma cells via secretion of cytokines, which play a critical role in modulating the malignant phenotypic changes of HCC [22,23]. In the present study, we proved the infiltration of HSCs into the HCC milieu relating to CCN3 paracrine of HCC, and CCN3 could elevate the cytokines paracrined by HSCs relating to enhanced HCC malignancy, all of which indicate the important role of CCN3 in the crosstalk between HCC and HSCs.…”

Hsa_circ_0005986 inhibits carcinogenesis by acting as a miR-129-5p sponge and is used as a novel biomarker for hepatocellular carcinoma

“…Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer [ 1 , 2 ]. HCC ranks the fourth in the frequency of cancer in men [ 3 ].…”

Remodeling of hepatic stellate cells orchestrated the stroma-derived oxaliplatin-resistance through CCN3 paracrine in hepatocellular carcinoma

“…Chen [23, 24] et al has shown that prostate cancer-derived CCN3 can induce M2 macrophage infiltration, relating to the construction of the prospective environment conducive to prostate cancer metastasis. Previously, we had reported that HSCs could interact with hepatoma cells via secretion of cytokines, which play a critical role in modulating the malignant phenotypic changes of HCC [6, 25]. In the present study, we proved the infiltration of HSCs into the HCC milieu relating to CCN3 paracrine of HCC, and CCN3 could elevate the cytokines paracrined by HSCs relating to enhanced HCC malignancy, all of which indicate the important role of CCN3 in the crosstalk between HCC and HSCs.…”