Evaluation of centrosome abnormalities and p53 inactivation in chemical induced hepatocellular carcinogenesis
Abstract:
Abnormal centrosome frequently found in human cancer is a major cause of mitotic defects and chromosome instability in cancer cells. Centrosome duplication is controlled in a cell cycle-specific manner, whereas cancer cells with dysregulation of centrosome duplication can survive and reenter the cell cycle through defective cell cycle checkpoint systems. Although numerous studies showed that centrosome amplification can be readily induced by loss or mutational inactivation of p53, however, the role of centrosomally localized p53 in the regulation of centrosome duplication had been enigma. To investigate the role of centrosome and p53 in the in vivo carcinogenesis, we performed immunofluorescence and Western blot analysis, respectively, to detect the alteration of centrosome and p53 status as well as immunohistochemical assay to detect cell proliferation in diethyl nitrosoamine (DENA) induced rat hepatocellular carcinoma (HCC). The frequencies of the centrosome abnormalities in HCC lesions were significantly higher than that of in their preneoplasitc counterparts as well as cell proliferation expression profile. Intriguingly, there was no correlation between centrosome abnormalities and cell proliferation. As for p53, the level of p53 increased in inflammation lesion, but decreased in hepatocirrhosis lesion, even undetectable in HCC lesion. These findings may imply that in inflammatory lesions aberration centrosome occurred irrespective of p53 background. However, the significantly increased percentage of cells with abnormal centrosome in hepatocirrhosis, particularly in HCC lesion concomitant with p53 inactivation and increased cell proliferation rate might synergistically contribute to carcinogenesis. Taken together, centrosome abnormalities were an early event prior to p53 inactivation in the time course of carcinogenesis, suggesting that p53 inactivation may not be the cause of centrosome aberration and centrosome may be a susceptible organelle responding to cellular insults.