The Significance Of Golgi Glycoprotein GP73 In Liver Diseases And Its Biological Function

GP73is a400-amino acid,73-kD resident Golgi-specific membrane protein expressed by biliary epithelial cells in normal liver. GP73expression in hepatocyte is up-regulated in patients with acute hepatitis, cirrhosis and hepatocellular carcinoma (HCC). This up-regulation occurred in response to viral and nonviral etiologies. Further studies demonstrated constitutive expression of GP73in cells of the epithelial lineage, especially in the prostate, gut, breast, thyroid, and within the central nervous system.Previous reports demonstrated an increased serum GP73(sGP73) levels in patients with hepatitis B virus (HBV) and hepatitis C virus (HCV)-related HCC in comparison with cirrhotic controls. The sensitivity and specificity of sGP73for HCC were superior to those of alpha-fetoprotein, especially in early HCC. These data indicate that serum GP73is a promising diagnostic marker for liver cancer. In addition to HCC, three studies have recently demonstrated an increased GP73expression in prostate cancer cells and urine GP73was diagnostically superior to serum prostate-specific antigen in prostate cancer. On the other hand, recent reports and our unpublished data indicate that GP73expression was not increased in Pea and breast cancer and sGP73levels were not increased in patients with colorectal cancer and breast cancer, this suggests that sGP73is not likely to become a pan-cancer marker.GP73is a type Ⅱ transmembrane protein with a single N-terminal transmembrane domain and a C-terminal coiled-coil domain located on the lumenal surface of the Golgi apparatus. The C-terminus contains a coiled-coil domain that is necessary for Golgi localization and retrieval to the cis-Golgi under steady-state conditions. Studies reported that mice carrying C-Terminally Truncated GP73results in decreased survival and severe epithelial abnormalities of the kidney and the liver.A recent report showed that GP73expression in HCC was significantly higher than that in the corresponding PCL and NL tissue at both protein and mRNA levels. The increased GP73protein level was associated with tumor size, vein invasion, and tumor differentiation. However, the functional importance of changes in GP73expression during liver cancer progression and the molecular mechanism mediating GP73function remain to be elucidated.Here we sought to determine whether GP73operates in the context of destruction of the tumor cells by host surveillance mechanisms or through a role of GP73in the process of the oncongenic transformation itself. We found that GP73stimulates the growth of tumor cells both in vitro and in vivo, GP73overexpression induces rapid Gl-S cell cycle progression, thus indicating that GP73has tumor oncogene properties. Focusing on the molecular mechanism underlying this, we show that GP73overepression induces innate immune response activation, lipid raft colocolization and cholerstrol accumulation, along with negative feedback regulation of TGF-β signalling pathway. Clinical studies showed that GP73may be a new serum biomarker for diagnosing liver disease related with acute damage, with postive correlation with serum ALT level. We therefore suggest that GP73is involved in a response that tends to stimulate the growth of these tumors.