Lost expression of ADAMTS5 protein associates with progression and poor prognosis of hepatocellular carcinoma

Abstract

Chongyi Li,1,2 Yanli Xiong,1 Xueqin Yang,1 Lin’ang Wang,1 Shiheng Zhang,1 Nan Dai,1 Mengxia Li,1 Tao Ren,1 Yuxin Yang,1 Shu-Feng Zhou,3 Lixia Gan,2 Dong Wang11Cancer Center, Daping Hospital and Research Institute of Surgery, 2Department of Biochemistry and Molecular Biology, The Third Military Medical University, Chongqing, People’s Republic of China; 3Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USAAbstract: Altered expression of ADAMTS5 is associated with human carcinogenesis and tumor progression. However, the role of ADAMTS5 in hepatocellular carcinoma (HCC) is unclear. This study analyzed ADAMTS5 expression in HCC tissues and tested for association with clinicopathological and survival data from HCC patients and then explored the role of ADAMTS5 in HCC cells in vitro. Paraffin blocks from 48 HCC patients were used to detect ADAMTS5 and vascular endothelial growth factor (VEGF) expression and microvessel density (MVD). A normal liver cell line and HCC cell lines were used to detect ADAMTS5 expression and for ADAMTS5 manipulation. ADAMTS5 cDNA was stably transfected into HCC cells and ADAMTS5 expression assessed by Western blot analysis. Tumor cell-conditioned growth medium was used to assess human umbilical vein endothelial cell migration and Matrigel tube formation. Xenograft assay was performed to determine the role of ADAMTS5 in vivo. The data showed that the expression of ADAMTS5 was reduced in HCC, which was inversely associated with VEGF expression, MVD, and tumor size and associated with poor overall survival of HCC patients. Lentivirus-mediated ADAMTS5 expression significantly inhibited tumor angiogenesis by downregulating in vitro expression of VEGF and inhibiting migration and tube formations, and also inhibited tumor growth and VEGF expression and reduced MVD in vivo in a mouse xenograft model. Taken together, these results suggest that ADAMTS5 plays a role in suppression of HCC progression, which could be further studied as a promising novel therapeutic target and a potential prognostic marker in HCC.Keywords: A disintegrin and metalloproteinase with thrombospondin motifs 5, tumor angiogenesis, tumor cell xenograft