Tanaka H, Fujii Y, Hirabayashi H, Miyoshi S, Sakaguchi M, Yoon H E, Matsuda H
First Department of Surgery, Osaka University Medical School, Japan.
Int J Cancer. 1998 Apr 17;79(2):111-5. doi: 10.1002/(sici)1097-0215(19980417)79:2<111::aid-ijc2>3.0.co;2-w.
The pathway consisting of retinoblastoma protein (pRB), cyclin D1 and p16 (RB pathway) which is involved in the phosphorylation of pRB plays an important role in G1/S progression. The disruption of this RB pathway has been reported in several types of human neoplasm. An immunohistochemical study of 101 non-small-cell lung cancers (NSCLCs) showed loss of p16 is in 47 tumors (46.5%) and loss of pRB in 42 tumors (41.6%). In 79 of 101 NSCLCs (78.2%), the expression of p16 and pRB was complementary (p < 0.0001). Methylation of the cdkn2 gene was detected in 50% of p16-negative tumors and in 11% of p16-positive tumors. Aberrant expression of cyclin D1 was found in 45 tumors (44.5%). The cyclin-D1-positive tumors had significantly higher Ki-67 indices than the cyclin-D1-negative tumors irrespective of the tumor p16 or pRB expression. Thus, 91 (90%) of 101 NSCLCs showed disturbed expression of at least 1 of the 3 components of the RB pathway. Our results suggest that the disruption of the RB pathway plays an important role in tumorigenesis in NSCLCs and that increased cyclin-D1 expression leads to strong proliferative activity which may over-ride the suppressive effect of p16 and pRB.
由视网膜母细胞瘤蛋白（pRB）、细胞周期蛋白D1和p16组成的通路（RB通路）参与pRB的磷酸化，在G1/S期进程中起重要作用。在几种人类肿瘤中已报道了该RB通路的破坏。一项对101例非小细胞肺癌（NSCLC）的免疫组织化学研究显示，47例肿瘤（46.5%）中p16缺失，42例肿瘤（41.6%）中pRB缺失。在101例NSCLC中的79例（78.2%）中，p16和pRB的表达呈互补关系（p<0.0001）。在50%的p16阴性肿瘤和11%的p16阳性肿瘤中检测到cdkn2基因甲基化。45例肿瘤（44.5%）中发现细胞周期蛋白D1异常表达。无论肿瘤p16或pRB表达如何，细胞周期蛋白D1阳性肿瘤的Ki-67指数均显著高于细胞周期蛋白D1阴性肿瘤。因此，101例NSCLC中有91例（90%）显示RB通路的3个组成部分中至少有1个表达紊乱。我们的结果表明，RB通路的破坏在NSCLC的肿瘤发生中起重要作用，并且细胞周期蛋白D1表达增加导致强烈的增殖活性，这可能会超过p16和pRB的抑制作用。
