Kang Yun Kyung, Kim Woo Ho, Jang Ja June
Department of Pathology, Inje University Seoul Paik Hospital and Seoul National University College of Medicine, Korea.
Hum Pathol. 2002 Sep;33(9):877-83. doi: 10.1053/hupa.2002.127444.
Aberrations of G1-S cell cycle arrest and TGF-beta/Smad pathway are critical events in human carcinogenesis. We studied alterations of both pathways by immunohistochemical staining for p53, p16, p27, cyclin D1, Rb and Smad4/Dpc4 in 42 intrahepatic cholangiocarcinomas (ICCs). Abnormal nuclear overexpression of p53 and cyclin D1 was noted in 15 (35.7%) and 26 (61.9%) cases, respectively. Total loss of p16, p27, Rb and Smad4 was detected in 15 (35.7%), 13 (31.0%), 5 (11.9%) and 19 (45.2%) cases, respectively. Forty cases (95.2%) showed aberrations of at least one of the pathways, of which 21 (50%) revealed abnormality in G1-S pathway only, 17 (40.5%) had abnormalities in both pathways and 2 (4.8%) had an abnormality in TGF-beta/Smad pathway only. Among the examined genes, loss of Smad4 was found to have a positive relationship with the pTNM stage (P < 0.05). The overall stage of the high-altered group (alterations in 2 to 5 of the genes, n = 29) was significantly higher than that of the low-altered group (alteration of one or no gene, n = 13) (P < 0.01). We also examined the expression of above genes in the accompanying biliary dysplasia and found out abnormal expression of p53, cyclin D1 or p16 in 7 out of 13 dysplastic lesions. Our data suggest that abnormal G1-S cell cycle and altered TGF-beta/Smad pathway are major events in cholangiocarcinogenesis. Moreover, there might be a possible cumulative effect of the alterations in the examined genes upon the clinical outcome of patients with resectable ICCs.
G1-S期细胞周期阻滞和转化生长因子-β（TGF-β）/Smad信号通路异常是人类致癌过程中的关键事件。我们通过免疫组化染色检测42例肝内胆管癌（ICC）中p53、p16、p27、细胞周期蛋白D1（cyclin D1）、视网膜母细胞瘤蛋白（Rb）和Smad4/Dpc4的表达，研究这两条信号通路的改变。p53和cyclin D1核异常高表达分别见于15例（35.7%）和26例（61.9%）。p16、p27、Rb和Smad4完全缺失分别见于15例（35.7%）、13例（31.0%）、5例（11.9%）和19例（45.2%）。40例（95.2%）至少有一条信号通路异常，其中21例（50%）仅G1-S信号通路异常，17例（40.5%）两条信号通路均异常，2例（4.8%）仅TGF-β/Smad信号通路异常。在检测的基因中，Smad4缺失与pTNM分期呈正相关（P < 0.05）。高改变组（2至5个基因改变，n = 29）总体分期显著高于低改变组（1个或无基因改变，n = 13）（P < 0.01）。我们还检测了上述基因在伴发的胆管发育异常中的表达，发现13个发育异常病变中有7个存在p53、cyclin D1或p16异常表达。我们的数据表明，G1-S细胞周期异常和TGF-β/Smad信号通路改变是胆管癌发生的主要事件。此外，所检测基因的改变可能对可切除ICC患者的临床预后产生累积效应。
