Nichols G E, Williams M E, Gaffey M J, Stoler M H
Department of Pathology, University of Virginia School of Medicine, Charlottesville, USA.
Mod Pathol. 1996 Apr;9(4):418-25.
Amplification of chromosome 11q13 leads to overexpression of a G1 cyclin gene, cyclin D1 (PRAD-1, CCND-1), in many non-cervical human carcinomas. Homology between cyclin D1 and human papillomavirus oncoprotein E7 binding sites for the retinoblastoma tumor-suppressor protein suggests that human papillomavirus oncoproteins cyclin D1, and other cell cycle regulatory proteins may act through a common mechanism in the pathogenesis of human cervical squamous cell carcinoma. We have examined 48 cases of cervical neoplasia by RNA-mRNA in situ hybridization for human papillomavirus mRNA and cyclin D1 mRNA and by immunohistochemistry for cyclin D1 protein expression. Hybridization demonstrated human papillomavirus RNA in all 48 cases with types 6, 16, or 18 in 2, 26, and 20 cases, respectively. Immunohistochemical detection using anti-cyclin D1 rabbit polyclonal antibody 19 demonstrated appropriate cyclin D1 expression at constitutive low levels in normal squamous epithelium and low-grade intraepithelial lesions. Immunohistochemical staining failed to demonstrate significant protein expression in any of the high-grade or invasive lesions. In contrast to the immunohistochemical results, in situ hybridization demonstrated cyclin D1 mRNA overexpression in three of five cases of low-grade squamous intraepithelial lesion, one of eight cases of high-grade squamous intraepithelial lesion, 14 of 18 cases of invasive squamous cell carcinoma, two of five cases of adenocarcinoma in situ, one of seven cases of invasive adenocarcinoma, and two of five cases of small cell undifferentiated carcinoma. Transcriptional activation of cyclin D1 can occur in vivo in human papillomavirus-associated invasive cervical carcinoma, but it does not seem to result in a steady state, increased level of cyclin D1 protein expression. These data indicate a limited role for cyclin D1 protein in the pathogenesis of human papillomavirus-associated invasive cervical squamous carcinoma. They support a model in which human papillomavirus proteins can circumvent cellular requirements for cyclin D1 in human cervical neoplasia.
11号染色体q13区域的扩增导致许多非宫颈癌的人类肿瘤中G1细胞周期蛋白基因——细胞周期蛋白D1（PRAD-1、CCND-1）的过表达。细胞周期蛋白D1与人乳头瘤病毒癌蛋白E7结合视网膜母细胞瘤肿瘤抑制蛋白的位点之间的同源性表明，人乳头瘤病毒癌蛋白、细胞周期蛋白D1以及其他细胞周期调节蛋白可能在人类宫颈鳞状细胞癌的发病机制中通过共同机制发挥作用。我们通过RNA-mRNA原位杂交检测人乳头瘤病毒mRNA和细胞周期蛋白D1 mRNA，并通过免疫组织化学检测细胞周期蛋白D1蛋白表达，对48例宫颈肿瘤进行了研究。杂交显示所有48例均有人乳头瘤病毒RNA，其中2例为6型，26例为16型，20例为18型。使用抗细胞周期蛋白D1兔多克隆抗体19进行免疫组织化学检测显示，在正常鳞状上皮和低级别上皮内病变中，细胞周期蛋白D1在组成性低水平上有适当表达。免疫组织化学染色未能在任何高级别或浸润性病变中显示出显著的蛋白表达。与免疫组织化学结果相反，原位杂交显示，在5例低级别鳞状上皮内病变中有3例、8例高级别鳞状上皮内病变中有1例、18例浸润性鳞状细胞癌中有14例、5例原位腺癌中有2例、7例浸润性腺癌中有1例以及5例小细胞未分化癌中有2例出现细胞周期蛋白D1 mRNA过表达。细胞周期蛋白D1的转录激活可在人乳头瘤病毒相关的浸润性宫颈癌体内发生，但似乎并未导致细胞周期蛋白D1蛋白表达的稳态增加。这些数据表明细胞周期蛋白D1蛋白在人乳头瘤病毒相关的浸润性宫颈鳞状癌发病机制中的作用有限。它们支持一种模型，即人乳头瘤病毒蛋白在人类宫颈肿瘤形成过程中可规避细胞对细胞周期蛋白D1的需求。
