High ADAM8 Expression is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma

Abstract

In this study,we investigated the ADAM8 expression in hepatocellular carcinoma (HCC) and its correlation with clinicopathologic features,including the survival of patients with HCC. Furthermore,we examined the biological processes regulated by ADAM8 during the development of using HepG2 cell line as a model system. We used immunohistochemistry to compare ADAM8 protein expression in HCC and normal liver tissues and further analyze the ADAM8 protein expression in clinicopathologically characterized 105 HCC cases.We stably knocked down the endogenous expression level of ADAM8 in HepG2 cells with specific shRNA-expressing lentiviral vector. Following the successful establishment of stable cells,we examined in vitro cell growth by MTT assay,anchorage-independent growth by soft-agar colony formation assay and cell migration/invasion by transwell and boyden chamber assay. And in addition,we also investigated the in vivo tumor growth by xenograft transplantation of HepG2 cells into nude mice. Protein expression level of ADAM8 was markedly higher in HCC tissues than that in the normal liver tissues (P = 0.0058).In addition,high expression of ADAM8 protein was positively correlated with serum AFP elevation,tumor size,histological differentiation,tumor recurrence,tumor metastasis,and tumor stage. Patients with higher ADAM8 expression showed a significantly shorter overall survival time than patients with low ADAM8 expression. Multivariate analysis suggested that ADAM8 expression might be an independent prognostic indicator (p = 0.016) for the survival of patients with HCC. ADAM8-specific shRNA (shADAM8) successfully knocked down its endogenous expression in HepG2 cells. Compared to the parental and control shRNA-transfected (shCtrl) HepG2 cells,the shADAM8 cells exhibited significantly reduced in vitro cell growth,anchorage-independent growth,cell migration and invasion (p < 0.05).In vivo,the xenograft transplants from shADAM8 cells gave rise to much smaller tumors as compared to those from shCtrl cells. High ADAM8 expression is associated with poor overall survival in patients with HCC. Down-regulation of ADAM8 inhibits the growth,anchorage-independent growth,migration and invasion of HepG2 cells. ADAM8 may be a potential target of antiangiogenic therapy for HCC.

MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7

“…15 An earlier study by our group showed that high expression of serum miR-17-5p is associated with poor prognosis in HCC patients. 16 However, the precise roles of miR-17-5p in liver fibrosis remain obscure at present. Here, we showed that miR-17-5p is increased in TGF-β1-induced HSCs as well as in carbon tetrachloride (CCl 4 )-treated rat liver fibrotic tissues.…”

Non-coding RNAs: New therapeutic targets and opportunities for hepatocellular carcinoma

“…lncRNAs could be characterized by qRT-PCR, Northern blot analysis or in situ hybridization [63] . In recent years, studies have shown that there are a large number of abnormally expressed miRNA in the serum of patients with HCC; some with low-level expressions of miR-16, let-7f, miR-21, miR-139, miR-101, miR-122 and miR-1, and some with high-level expressions of miR-17-5p, which probably indicated the recurrence of HBV-related HCC prognosis [85] . Tan et al also identified that the miRNAs are differentially expressed in cirrhosis that evolved into HBV-related HCC by analyzing miRNAs that exhibit differential expressions such as miR-122-5p, miR-199a-5p, miR-486-5p, miR-193b-5p, miR-206, miR-141-3p, miR-192-5p and miR-26a-5p [86] .…”

Emerging role of microRNAs in the treatment of hepatocellular carcinoma

“…Hbx protein decreases levels of several tumor suppressor miRNAs, such as miR-34 and let-7, 37 while HBx RNA directly downregulates miR-15a and miR-16-1. 38 Moreover, upregulated gene, upregulation of which is induced by HBx, could induce miR-148a overexpression and promote cell cycle progression and cell migration. 39,40 The mechanisms of miRNA deregulation by hepatitis C virus have been less extensively studied.…”