CCN1/Cyr61 enhances the function of hepatic stellate cells in promoting the progression of hepatocellular carcinoma

Li,Zhi‑Qiang; Wu,Wei‑Ru; Zhao,Chen; Zhao,Chen; Zhang,Xiao‑Li; Yang,Zhong; Pan,Jing; Si,Wei‑Ke

doi:10.3892/ijmm.2017.3356

CCN1/Cyr61 enhances the function of hepatic stellate cells in promoting the progression of hepatocellular carcinoma

Authors:
- Zhi‑Qiang Li
- Wei‑Ru Wu
- Chen Zhao
- Xiao‑Li Zhang
- Zhong Yang
- Jing Pan
- Wei‑Ke Si
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Affiliations: Department of Clinical Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P.R. China, The First Affiliated Hospital, Chongqing Medical University, Chongqing 400042, P.R. China
Published online on: December 29, 2017 https://doi.org/10.3892/ijmm.2017.3356
Pages: 1518-1528
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)‑producing cells in liver fibrosis. Activated HSCs stimulate the proliferation and migration of hepatocellular carcinoma (HCC) cells. Cysteine‑rich 61 (CCN1/Cyr61) is an ECM protein. Our previous studies demonstrated that the expression of CCN1 was significantly higher in benign hepatic cirrhosis tissue and cancer‑adjacent hepatic cirrhosis tissues. CCN1 is a target gene of β‑catenin in HCC and promotes the proliferation of HCC cells. The present study aimed to examine whether CCN1 can activate HSCs and affect the function of activated HSCs in promoting the progression of HCC. CCN1 expression was determined during the progression of liver fibrosis in a mouse model. LX‑2 cells, which were infected with adenoviruses AdCCN1 or AdRFP, and HepG2 cells were co‑cultured or subcutaneously co‑implanted into in nude mice. MTT assay, Crystal Violet staining, Boyden chamber, matrigel invasion and monolayer scratch assays were used to analyze the proliferation, migration and invasion capability of HepG2 cells. Xenograft sizes were measured and histological analyses were performed by hematoxylin and eosin, immunohistochemical, immunefluorescence and Sirius Red staining. It was demonstrated that the expression of CCN1 was continually increased in liver fibrosis and the that expression may be correlated with the progression of liver fibrosis. CCN1 affected the function of LX‑2 and enhanced the effect of LX‑2 on promoting the viability, migration and invasion of HepG2 cells in vitro. CCN1 enhanced the effect of LX‑2 on promoting the growth of HepG2 xenografts in vivo. CCN1 also affected the function of activated HSCs and regulated the formation of the xenograft microenvironment, including fibrogenesis and angiogenesis, which are beneficial for the progression of HCC. These findings demonstrated that CCN1 may be involved in the progression of the hepatic cirrhosis‑HCC axis through regulating HSCs.

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