The risk factor of gallbladder cancer: Hyperplasia of mucous epithelium caused by gallstones associates with p16/CyclinD1/CDK4 pathway

Backgrounds: The mucosa of gallbladder stimulated with gallstones and accompanied with abnormalities in bile composition, is the origin of biliary disease, which could induce metaplasia. simple hyperplasia, atypical hyperplasia and even carcinoma in situ and invasive carcinoma in gallbladder mucosa. Methods: To determine the disorder of the balance between cell proliferation and cell cycle or apoptosis in gallbladder cancer accompanied with gallstones, removal of the gallbladder due to gallstones specimens of 88 cases were collected randomly, including a variety of 54 cases for hyperplasia, 27 cases for gallbladder cancer and 7 cases for normal gallbladder. The expressions of key cell cycle factors were detected by in situ hybridization, immunohistochemistry and Western blot. Results: The expressions of CDK4 and Cyclin D1 increased along with progression of gallbladder mucosa hyperplasia; and showed highest expression in cancer group. On the contrary, p16 decreased to the lowest level in gallbladder cancer. The increased apoptotic index analyzed by TUNEL assay rose along with malignant degree to the highest level in undifferentiated carcinoma. Conclusions: Our results suggest that changes of these signals have effect on breaking the balance of proliferation and death of gallbladder epithelial cells, even on inducing gallbladder cancer. (C) 2011 Elsevier Inc. All rights reserved.