Nakajima Tomoki, Moriguchi Michihisa, Mitsumoto Yasuhide, Sekoguchi Satoru, Nishikawa Taichirou, Takashima Hidetaka, Watanabe Tadashi, Katagishi Tatsuo, Kimura Hiroyuki, Okanoue Takeshi, Kagawa Keizo
Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.
Mod Pathol. 2004 Jun;17(6):722-7. doi: 10.1038/modpathol.3800115.
Centrosome duplication is controlled in a cell cycle-specific manner and occurs once every cell cycle, thereby ensuring the balanced segregation of chromosomes during the mitotic phase. Numerical or structural abnormalities can arise in the centrosomes of malignant cells. Under defective cell cycle checkpoint systems, cancer cells with abnormal centrosomes can survive and re-enter the cell cycle, promoting unbalanced chromosome segregation and genetic instability. We investigated the centrosome aberrations in 33 patients diagnosed with hepatocellular carcinoma (HCC), using fluorescent pericentrin immunostaining. We also studied the p53 mutation, proliferative activity, and DNA ploidy in these cases. In normal hepatocytes, one centrosome was identified per cell as a round dot, usually in the vicinity of the nuclear membrane. However, in cancer cells from HCC tissue, several patterns of centrosome abnormalities occurred, including supernumerary centrosomes and centrosomes with an abnormal shape and size. Although the frequency of abnormal centrosomes in each tissue was relatively low compared with previous reports in other cancers, nevertheless, centrosome aberration was found in 30 out of 33 HCC tissues. The percentage of tumor cells with abnormal centrosomes was significantly higher in the nondiploid tumors (15.8+/-15.9 per thousand ) than in the diploid tumors (5.4+/-5.1 per thousand ) (P<0.05), and tended to be higher in the tumors with p53 mutation (11.6+/-13.1 per thousand ) than in those with wild-type p53 (5.6+/-6.8 per thousand ). Furthermore, 82% of nondiploid tumors exhibited p53 mutation, whereas only 41% of diploid tumors showed p53 mutation. The percentage of tumor cells with centrosome abnormalities were not related to tumor stage, size or proliferative activity. Therefore, our results indicate that hepatic cancer cells, under centrosome aberration and a defective checkpoint system possibly caused by p53 mutation, have the potential for genetic instability and aggressive behavior. This potential effect occurs irrespective of the tumor size or stage.
中心体复制以细胞周期特异性方式受到调控，且每个细胞周期发生一次，从而确保有丝分裂期染色体的平衡分离。恶性细胞的中心体可能出现数量或结构异常。在有缺陷的细胞周期检查点系统下，中心体异常的癌细胞能够存活并重新进入细胞周期，促进染色体分离失衡和遗传不稳定。我们使用荧光 pericentrin 免疫染色法，研究了 33 例诊断为肝细胞癌（HCC）患者的中心体畸变情况。我们还研究了这些病例中的 p53 突变、增殖活性和 DNA 倍性。在正常肝细胞中，每个细胞可识别出一个中心体，呈圆形小点，通常位于核膜附近。然而，在 HCC 组织的癌细胞中，出现了几种中心体异常模式，包括中心体数量过多以及形状和大小异常的中心体。尽管与先前其他癌症的报道相比，每个组织中异常中心体的频率相对较低，但在 33 个 HCC 组织中，仍有 30 个发现了中心体畸变。非二倍体肿瘤中具有异常中心体的肿瘤细胞百分比（每千个中有 15.8±15.9 个）显著高于二倍体肿瘤（每千个中有 5.4±5.1 个）（P<0.05），并且 p53 突变的肿瘤中（每千个中有 11.6±13.1 个）具有异常中心体倾向于高于野生型 p53 的肿瘤（每千个中有 5.6±6.8 个）。此外，82%的非二倍体肿瘤表现出 p53 突变，而只有 41%的二倍体肿瘤显示 p53 突变。具有中心体异常的肿瘤细胞百分比与肿瘤分期、大小或增殖活性无关。因此，我们的结果表明，在可能由 p53 突变引起的中心体畸变和有缺陷的检查点系统下，肝癌细胞具有遗传不稳定和侵袭性行为的潜力。这种潜在影响与肿瘤大小或分期无关。
