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

Abstract

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.

Polymorphisms of a Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 and Aflatoxin B1–Related Hepatocellular Carcinoma

“…It was found that this polymorphism was associated with the downregulation of ADAMTS5 expression, increasing MVD, tumor progression, dedifferentiation, and metastasis. A recent in vivo and in vitro study has shown that downregulation of this gene accelerates hepatocellular carcinoma angiogenesis and carcinogenesis by modifying VEGF expression (14). The survival analysis further indicated that the rs2830581 polymorphism was associated with poor outcome of hepatocellular carcinoma patients, highlighting the potential roles of this polymorphism in predicting the prognosis of hepatocellular carcinoma induced by AFB1 exposure.…”

“…Previously, studies have suggested that ADAMTS5 may be involved in the development and progression of cancers affecting the breast, prostate, brain, colorectal tissue, and liver (10,14,16,(27)(28)(29). Porter and colleagues (27) found that ADAMTS5 expression in breast cancer tissues was downregulated in cancerous tissues with respect to nonneoplastic mammary tissue, irrespective of the heterogeneity of the samples and the tumor type or grade.…”

“…Kim and RomanGomez (10,16) observed that the ADAMTS5 gene exhibited hypermethylation in colorectal cancer and T-cell acute lymphoblastic leukemia. Additional studies have indicated that it may be possible for this gene to suppress tumor growth and progress (9,14,16). In contrast, other reports indicated that ADAMTS5 expression was upregulated in human glioblastoma compared with normal brain tissues and promoted glioma cell invasiveness in culture (28).…”

“…From previous reports, it is known that ADAMTS5 expression is capable of regulating hepatocellular carcinoma angiogenesis (14). Thus, we explored how expression of ADAMTS5 rs2830581 polymorphism affected MVD (Fig.…”

“…Recently, a preponderance of evidence has implicated aberrant ADAMTS5 expression in the development and progression of some tumors including breast cancer, colorectal cancer, glioblastoma, hepatocellular carcinoma, and T-cell acute lymphoblastic leukemia (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Despite the collected data, the association of altered ADAMTS5 expression and genetic variants of AFB1-related hepatocellular carcinoma remains to be elucidated.…”