Abstract: OBJECTIVE: To detect expression of mutations in tumor-related genes,such as Kras,Trp53 and Smad4 in pancreatic tissues of diet-induced obese mice and to explore whether obesity is associated with genome instability in the pancreas. METHODS: Male C57BL/6 mice were fed normal chow diet and high-fat diet for 24 weeks. The body weight,food intake,body composition and plasma lipid were measured. Pancreatic genomic DNA was extracted and the exon 2 of Kras,exon 8 of Trp53 and exon 9 of Smad4 were amplified by using high-fidelity PCR. The PCR products were then subjected to the Sanger sequencing protocol. Cell proliferation was assessed by qPCR and immunohistochemistry for Ki67. RESULTS: Intake of 24 weeks of high-fat diet led to severe obesity in mice. High-fat diet feeding increased the body weight,fat mass,lean mass,hepatosomatic index and body-fat ratio of epididymal (P < 0.05). Body weight gain in high-fat diet group was significantly higher than those of chow diet group from eating the same weight of food(P < 0.05). Plasma lipid such as triglyceride,total cholesterol and low density lipoprotein cholesterol were significantly higher in high-fat diet group(P < 0.05). Moreover,the level of Ki67 mRNA was increased in the high-fat diet group(P < 0.05). There were several Ki67 positive cells in pancreatic duct,indicating that proliferation of pancreatic cells in obese mice were elevated. We detected 1 locus mutation in the Kras gene in 1 out of 50 samples (rate:2%). There was no mutation in the other two genes. CONCLUSION: Obesity resulted in instability of Kras gene in pancreatic tissue,which could play a role in the initiation and progression of pancreatic cancer.

Key words: obesity, pancreatic cancer, mutation, mice