Chen Y, Kong Q
School of Life Science and Technology, Henan Institute of Science and Technology, PR China.
Neoplasma. 2009;56(2):169-76. doi: 10.4149/neo_2009_02_169.
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.
centrosome, p53, hepatocellular carcinoma, cell proliferation.
人类癌症中经常发现的异常中心体是癌细胞有丝分裂缺陷和染色体不稳定的主要原因。中心体复制以细胞周期特异性方式受到控制，而中心体复制失调的癌细胞可以通过有缺陷的细胞周期检查点系统存活并重新进入细胞周期。尽管大量研究表明，p53的缺失或突变失活可轻易诱导中心体扩增，然而，中心体定位的p53在中心体复制调控中的作用一直是个谜。为了研究中心体和p53在体内致癌过程中的作用，我们分别进行了免疫荧光和蛋白质印迹分析，以检测中心体和p53状态的改变，并进行免疫组织化学分析以检测二乙基亚硝胺（DENA）诱导的大鼠肝细胞癌（HCC）中的细胞增殖。HCC病变中中心体异常的频率明显高于其癌前对应物以及细胞增殖表达谱。有趣的是，中心体异常与细胞增殖之间没有相关性。至于p53，p53水平在炎症病变中升高，但在肝硬化病变中降低，在HCC病变中甚至无法检测到。这些发现可能意味着在炎症病变中，中心体畸变的发生与p53背景无关。然而，肝硬化中中心体异常细胞的百分比显著增加，特别是在伴有p53失活和细胞增殖率增加的HCC病变中，可能协同促进致癌作用。综上所述，在致癌过程中，中心体异常是p53失活之前的早期事件，这表明p53失活可能不是中心体畸变的原因，中心体可能是对细胞损伤作出反应的敏感细胞器。
中心体；p53；肝细胞癌；细胞增殖
