EFNA1 ligand and its receptor EphA2: potential biomarkers for hepatocellular carcinoma

Abstract

Novel biomarkers are needed for early detection and progression evaluation of hepatocellular carcinoma (HCC). The purpose of this study was to identify useful biomolecular markers for HCC. The 26 genes that encode membrane or secretory proteins were identified from cDNA microarray data. We further examined the expression of EFNA1 and its receptor EphA2 and determined their biological implications during the development and progression of HCC. The EFNA1 mRNA was overexpressed in most HCCs as compared with its expression in corresponding nontumor tissues (36 out of 40 cases, 90%), but EphA2 expression was noted in only half of the HCC tissues (20 of 40 cases, 50%). In most of the hepatoma cell lines, the EFNA1 protein expression was positively associated with alpha-fetoprotien (AFP) expression but inversely associated with EphA2 expression. Furthermore, EFNA1 levels were detectable in the supernatant of the cultured hepatoma cells and in the serum of patients with HCC. In contrast, EphA2 expression was prominent in highly invasive hepatoma cells, and its overexpression was significantly correlated with decreased differentiation (r 5 0.0248, p < 0.010) and poor survival (p 5 0.0453) for HCC patients. EFNA1 and EphA2 may be useful serum markers for the detection of HCC development and progression, respectively.Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and it is known to be the third most common cause of cancer-related mortality. 1 The incidence of HCC is increasing in Western countries such as Europe and the Unites States. 2 One of the reasons for the high mortality is that HCC tumors are commonly detected at a stage when curative resection is no longer feasible because of intrahepatic and extrahepatic metastasis. The diagnosis of HCC currently relies on observation of a liver mass in radiology imaging studies such as ultrasonography, computed tomography scanning or magnetic resonance imaging. However, the diagnosis of small lesions is relatively inaccurate. 3 The only approach to screen for the presence of HCC in a high risk-population is the combination of serum alpha-fetoprotein (AFP) level determination and ultrasonography. 4,5 However, the AFP level test has low sensitivity and specificity, particularly in patients with smaller HCCs. Several biomarkers such as Desgamma carboxyprothrombin (DCP), lens cularis agglutininreactive AFP and glypican-3 (GPC3) have yet to be validated for their abilities to detect an early HCC. 6 Therefore, there is an urgent need to identify adequate biochemical markers for early detection and to evaluate the progression of HCC. Genome-wide microarray analysis offers a systemic approach for obtaining comprehensive information on the transcriptional profiles of HCC. Using microarray technology, we previously determined the molecular nature of multistep hepatocarcinogenesis and the specific genetic changes associated with the oncogenic differentiation of HCC. 7 In our previous study, we used a modified analytical approach to identify several molecular marke...

Association between ephrin-A1 mRNA expression and poor prognosis after hepatectomy to treat hepatocellular carcinoma

“…EFNA1 ligand and its receptor, EPHA2, were expressed and upregulated in both tumor cells and tumor vessels. In line with the results of the present study, hypoxic conditions are known to upregulate the expression of EFNA1 in hepatoma cells in vitro (34,35). We previously reported that silencing of EFNA1 in tumor cells inhibits the migration, invasion and proliferation of tumor cells themselves and also inhibits the migration of endothelial cells in coculture experiment (32).…”

“…One report revealed that expression of EFNA1 and AFP was strongly associated and that they induced the expression of genes related to the cell cycle, angiogenesis and cell-cell interactions (34). The other report showed that EFNA1 mRNA was overexpressed in 90% of HCC cells and EPHA2 expression was significantly correlated with poor survival in HCC patients (35). Both reports indicated that EFNA1 and its receptor, EphA2, promote proliferation and invasiveness in HCC.…”

Specific Markers for Hepatic Progenitor Cells

“…Meanwhile, EFNA1 is over expressed in tumor cells, i.e., HCC and related to endothelial cell migration, tumor progression, angiogenesis (Cui et al, 2010). Hao et al (2013) found expression of EFNA1 in ductular reaction is correlated to AFP.…”

Overexpression and correlation of HIF-2α, VEGFA and EphA2 in residual hepatocellular carcinoma following high-intensity focused ultrasound treatment: Implications for tumor recurrence and progression

“…Erythropoietin-producing hepatocellular A2 (EphA2) is also implicated in HCC. It has been found that EphA2 expression is prominent in invasive hepatoma cells and is significantly correlated with poor survival of HCC patients, suggesting that EphA2 is a potential serum marker for the detection of HCC development and progression (12). Furthermore, there is increasing evidence that high-levels of EphA2 may promote angiogenesis, tumor growth and invasion (13,14).…”