The Mrna Expression Of Unfolded Protein Response Genes Atf6, GRP78 And XBP1 In Human Hepatocellular Carcinoma And Its Clinical Implications

Objective To investigate the mRNA expression of unfolded protein response (UPR) genes GRP78 and ATF6 in human hepatocellular carcinoma and its possible relationship with tumor development and clinical prognosis.Methods The expression of GRP78 and ATF6 genes were observed with immunohistochemistry and RT-PCR was performed to compare the expression levels of the two hypotypes of XBP1 mRNA in 100 samples of hepatocellular carcinoma (HCC) cells resected in surgery and 32 samples of non-hepatoma cells.Statistic methods were used to analyse the results.Result GRP78 expression was detected in 70% HCC cells, while the proportion was 37.5% in non-hepatoma cells (P<0.05). The expression rates in high, medium, and low differentiated HCC cells were 44%, 57%, and 87% respectively; significantly higher in pathological low differentiated HCC cells than in high and medium differentiated cells (P<0.05). The expression rate of GRP78 was 41.7% in cells at I and II phase, 78.9% in those at III and IV phase (P<0.05).ATF6 was found expressed in 64% HCC cells, but only in 31.25% non-hepatoma cells (P<0.05). The expression rates in high, medium, and low differentiated HCC cells were 33.3%, 40%, 88.4% respectively; significantly higher in low differentiated cells than in high and medium differentiated ones (P<0.05). In HCC cells at I and II phase, 33.3% expressed ATF6, while that rate in those at III and IV phase was 73.7% (P<0.05).The expression level is closely related with the malignancy and invasion of the tumor cell.The result of Real-time PCR shows that the expression level of XBP1-s gene was up-regulated by 10.59 times in the HCC cell than in the normal hepatic cell, while the levels of XBP1-u gene show no obvious difference in these two types of cells.Conclusions In HCC, the UPR may be activated, and the activation of ATF6 pathway and splicing of the XBP1 mRNA was identified, which may demonstrate the ERS improve the malignancy and invasive ability of the hepatic tumor which might be negatively correlated with the prognosis of HCC patients.