Up-regulation of glycosylphatidylinositols anchor attachment protein (GAA1) is associated with poor prognosis of hepatocellular carcinoma

Abstract

Many cell-surface proteins are anchored to the membrane with posttranslational attachment of glycosyl-phosphatidylinositol (GPI) anchoring to their carboxyl-terminus. Targets of GPI attachment are diverse and mediate various functions such as cell-to-cell adhesion, nutrient uptake, signal transduction and regulation of complement activity. Recently, GPI anchor has been suggested as a potential transfer technique to modify the tumor membrane for cancer therapy. For example, IL-12, IL-2 and CD80 are presented on the cell surface by GPI-anchoring to trigger anti-tumor immune response. This covalent attachment process is controlled by the heterotetrameric GPI transamidase (GPIT) complex which function may hinder the efficiency of the transfer. We have preformed a genome-wide expression profile of hepatocellular carcinoma (HCC) and their non-tumor liver tissues using cDNA microarray approach (Mol Biol Cell 13:1929-39, 2002). GPI anchor attachment protein 1 (Gaa1), the major subunit of the GPIT complex, was found to be up-regulated in tumor tissues. In the current study, we have evaluated the expression levels of Gaa1 in 64 pairs of paralleled tumor and adjacent non-tumor tissues using real-time quantitative RT-PCR. Consistent with our microarray data, Gaa1 was up-regulated in 60/64 (94%) of HCC tissues when compared with their adjacent non-tumor counterparts (P<0.001 by Student’s t-test). This up-regulation was closely related to its poor cellular differentiation (Edmondson grading system) (P<0.005) which is associated with aggressive tumor type and poor prognosis. Furthermore, the level of Gaa1 was significantly higher in patients who had shorter over-all survival. The median survival time of the low expression group was undetermined as the majority of the patients are still alive. The median survival time of the high expression group was 47.5 months (P<0.05 by log rank test). Multivariate analysis indicated that Gaa1 is an independent prognostic marker together with pTNM staging system for overall survival. Our current finding has indicated that regulation of GPI attachment may play an important role in tumor progression. Further investigation of this regulation, especially on the role of Gaa1 in HCC may help to elucidate the role of GPI attachment in HCC and provide evidence on the use of GPI-anchored protein for cancer therapy.