Overexpression of PrP^C and Its Antiapoptosis Function in Gastric Cancer

Abstract

Cellular prion protein (PrP^C), a glycosylphosphatidylinositol-anchored membrane protein, was found in our lab to be widely expressed in gastric cancer cell lines. In order to evaluate its biological significance in human gastric cancer, we investigated its expression in a large series of gastric tissue samples (n = 124) by immuno histochemical staining with the monoclonal antibody 3F4. Compared with normal tissues, gastric adenocarcinoma showed increased PrP^C expression, correlated with the histopathological differentiation (according to the WHO and Lauren classifications) and tumor progression (as documented by pTNM staging). To better understand the underlying mechanism, we introduced the PrP^C and two pairs of RNAi into the poorly differentiated gastric cancer cell line AGS and found that PrP^C suppressed ROS and slowed down apoptosis in transfected cells. Further study proved that the apoptosis-related protein Bcl-2 was upregulated whereas p53 and Bax were downregulated in the PrP^C-transfected cells. A reverse effect was observed in PrP^C siRNA-transfected cells. These results strongly suggested that PrP^C might play a role as an effective antiapoptotic protein through Bcl-2-dependent apoptotic pathways in gastric cancer cells. Further study into the mechanism of these relationships might enrich the knowledge of PrP, better our understanding of the nature of gastric carcinoma, and further develop possible strategies to block or reverse the development of gastric carcinoma.

The evaluation of 23-bp and 12-bp insertion/deletion within the PRNP gene and their effects on growth traits in healthy Chinese native cattle breeds

“…Isler et al (2006) showed a correlation between the variation in PrP genotypes and the longissimus muscle depth of Dorset × Romanov sheep. Moreover, it had identified that overexpression of PrP C and its antiapoptosis function in gastric cancer, suggesting that PrP(C) might play a role as an effective antiapoptotic protein through Bcl-2-dependent apoptotic pathways in gastric cancer cells (Liang et al 2006). Therefore, these genotypes in these two indel loci of PRNP should be considered when selecting the healthy and excellent individuals.…”

Prion protein ablation increases cellular aggregation and embolization contributing to mechanisms of metastasis

“…A positive correlation between PrP C expression and tumor progression was found in a series of gastric tumor samples, 19,20 where overexpression of PrP C increased tumor cell proliferation through the PI3K/AKT/ Cyclin D1 signaling pathways. 23 Similarly in glioblastomas, STI1 binding to PrP C was shown to induce cell proliferation.…”

“…18 PrP C overexpression in gastric tumor cell lines has also been associated with increased expression of Bcl-2, and decreased expression of p53 and Bax, indicating a possible increase in resistance to programmed cell death. [18][19][20] In the absence of PrP C expression, resistance to TRAIL-induced apoptosis was inhibited in breast adriamycinresistant carcinoma cells. 21 In addition, breast tumor lacking estrogen receptor and PrP C expression show a high sensitivity to adjuvant chemotherapy.…”

Prion protein scrapie and the normal cellular prion protein

“…Consistant with this, overexpression of PrP C has also been reported in a number of human gastric cancer cell lines including SCG7901 and AGS. 73,134,135 PrP C was also found to be expressed in gastric carcinoma tissues using immunohistochemical staining. 73,134 Du et al 73 discovered that PrP C is expressed more strongly in gastric adenocarcinoma tissues than in adjacent non-tumorous tissues and is weakly, or not expressed, in normal gastric mucosa.…”

“…73,134,135 PrP C was also found to be expressed in gastric carcinoma tissues using immunohistochemical staining. 73,134 Du et al 73 discovered that PrP C is expressed more strongly in gastric adenocarcinoma tissues than in adjacent non-tumorous tissues and is weakly, or not expressed, in normal gastric mucosa. PRNP was found to be over-expressed in pancreatic ductal adenocarcinoma (PDAC) in a microarray study by Han et al 136 Another study investigated 7 human PDAC cell lines to determine whether PrP C is overexpressed.…”