S2050 Prostanglandin E2 Receptors Are Involved in Nicotine-Induced Gastric Tumor Growth

Abstract

We have previously determined that the small GTPase Rab25 regulates membrane recycling in epithelial cells. However, little is known whether membrane recycling and vesicle trafficking pathways influence epithelial tissue transformation and neoplasia. Based on the hypothesis that membrane recycling is necessary to maintain epithelial cell polarity, we sought to determine the effects of Rab25 loss on the development of colonic neoplasia. We therefore bred Rab25 knockout mice in the C57BL/6 background onto the ApcMin/+ mouse. To understand the function of Rab25, we have developed a mouse model for deletion of the Rab25 gene product. To assess the effects of Rab25 loss on the development of colonic neoplasia, we have bred Rab25 knockout mice on the C57BL/6 background onto the ApcMin/ +mouse. At 4months of age, Rab25-/-ApcMin/+mice showed 175 intestinal polyps compared with 45.4 in Rab25+/+ApcMin/+ mice and 98.5 in Rab25+/-ApcMin/+ mice (p<0.01). In the colon, Rab25-/-ApcMin/+ 4.7 colon tumors compared with only 1.9 in Rab25+/+ApcMin/ + mice (p<0.01) and 3.5 in Rab25+/-ApcMin/+ mice. Histopathological analysis of the polyps in Rab25-/-ApcMin/+ mice showed diffuse and fused microadenomas with high mitotic index compared to control. We also sought to examine Rab25 gene expression in a large panel of colon cancer tumor isolates by mining a previously characterized series of mouse and human tumor gene microarray expression profile data. Expression of Rab25 was significantly decreased in colon adenocarcinomas (p<0.03) independent of Duke's stage. In addition, Kaplan-Meier analysis demonstrated that lower expression of Rab25 correlated with significantly lower survival (p<0.035). These results show that the loss of Rab25 promotes the initiation of intestinal polyposis inmice and reductions in Rab25 correlate with poor prognosis in human colorectal cancer. These findings indicate that aberrations in vesicle trafficking may promote intestinal neoplasia.