Effect of cigarette smoke exposure and mutant Kras overexpression on pancreatic cell proliferation

Abstract

Pancreatic cancer is the fourth leading cause of cancer-associated mortality. The major risk factor for pancreatic cancer is cigarette smoking. Kras mutations are commonly observed in human pancreatic cancers. The present study examined the hypothesis that exposure to cigarette smoke and overexpression of a mutant Kras gene in the pancreas affects pancreatic cell proliferation in mice. Mice overexpressing the mutant Kras gene (KRas^G12D) in the pancreas as well as wild-type mice were exposed to environmental tobacco smoke for 2 weeks. Overexpression of mutant Kras increased cell proliferation in pancreatic ductal, acinar and islet cells. Notably, cigarette smoke exposure decreased cell proliferation in pancreatic ductal and acinar cells, and had no effect in islet cells. Cigarette smoke did not affect pancreatic protein levels of tumor necrosis factor (TNF)α, p53, or cyclin D₁, but mutant Kras overexpression slightly decreased TNFα and p53 protein levels. Therefore, pancreatic cell proliferation in mice overexpressing mutant Kras is associated with the later development of pancreatic tumors, but effects of cigarette smoke on pancreatic cell proliferation do not provide a good model for human pancreatic carcinogenesis.

Keywords: Kras; cell proliferation; cigarette smoke; pancreas.

Figure 1.

Labeling indices in pancreatic (A) ductal, (B) acinar and (C) islet cells. Results are expressed as the mean ± standard error, with n=7 or 8. *Significant differences due to mutant Kras overexpression are indicated with an asterisk; ^{^}significant differences in smoke-exposed mice (P<0.05). Cre, Cre recombinase.

Figure 2.

(A) The western blot analysis shows expression of TNF-α, p53, cyclin D1 and β-actin in pancreas tissue lysates (A). The graphs show quantitative analysis of protein expression for (B) TNF-α, (C) p53, and (D) cyclin D1 using ImageJ. β-actin was used as the loading control. Results are expressed as the mean ± standard error, with n=3 or 4. TNF-α, tumor necrosis factor α; R, Kras; C/Cre, Cre recombinase; AU, arbitrary unit.