villin阳性胃祖细胞中PPARdelta过表达在小鼠中驱动胃肿瘤发生且独立于幽门螺杆菌感染

Background Overexpression of the single gene PPARdelta in villin-positive gastric progenitor cells (VGPCs) has been shown to induce gastric adenocarcinoma (GAC) in villin-PPARdelta mice. However, PPARdelta overexpression alone in colonic epithelial cells or pancreatic progenitor cells in mice fails to initiate tumorigenesis but dramatically accelerated tumor development in the colon and pancreas. These findings raise the question of whether additional factors cooperate with PPARdelta to drive GAC. H. pylori infection is a strong risk factor for human GAC. In modified SPF barrier where villin-PPARdelta mice are housed, helicobacter species is not excluded and presumed to be endemic. Whether such helicobacter infection contributes to PPARdelta-driven GAC remains unknown. Methods A new villin-PPARdelta mouse line was generated via in vitro fertilization using frozen sperm of villin-PPARdelta mice and housed in helicobacter-free barrier. At 4 weeks of age, half of the mice remained in helicobacter-free barrier (villin-PPARdelta-L1), while the other half were transferred to modified SPF barrier, where helicobacter species is commonly detected in the gastrointestinal tract of housed mice (villin-PPARdelta-L2). These mice, along with the previous villin-PPARdelta mouse line that had been maintained in modified SPF barrier for years (villin-PPARdelta-L3), were followed for 25, 35, and 55 weeks (n =10-12 mice per group). Wild type (WT) littermates from each line were served as controls. All mice were evaluated for tumor multiplicity and subjected to histologic examination. Helicobacter species was assessed by detecting 16S rRNA genes from genomic DNA extracted in mouse stomach contents and stools using qPCR/PCR. Results Helicobacter species was not detectable in villin-PPARdelta-L1 mice at all ages and villin-PPARdelta-L2 mice at 10 and 25 weeks but were detected in villin-PPARdelta-L2 mice at 35 and 55 weeks and villin-PPARdelta-L3 mice at all ages. Longitudinal follow-up revealed that gastric tumorigenesis progressed in an age-dependent manner. Gross lesions were initially found in the lesser curvature of the gastric corpus at 25 weeks and eventually expanded to occupy the whole gastric corpus at 55 weeks. All mice examined at ≥ 25 weeks developed at least gastric hyperplasia. At 35 weeks, approximately 60% of mice developed low-grade or high-grade gastric dysplasia, and by 55 weeks, around 70% developed GACs, including 30% with large, locally invasive GACs. Chronic inflammation was present in gastric lesions and positively correlated with tumor progression. No significant differences in gastric inflammation and tumorigenesis were observed among three villin-PPARdelta mouse lines. None of WT controls developed gastric tumors. Conclusions PPARdelta overexpression in VGPCs drive gastric tumorigenesis independent of helicobacter infection in mice, suggesting that PPARdelta may be a potential therapeutic target for GAC.