Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany.
Int J Cancer. 2012 Jan 15;130(2):388-94. doi: 10.1002/ijc.26017. Epub 2011 Jun 10.
Diffuse overexpression of p16(INK4a) in basal and parabasal cells of cervical epithelium is a hallmark of human papillomavirus-mediated transformation. Focal p16(INK4a) expression is occasionally observed in nondysplastic epithelium. In normal cells, expression of p16(INK4a) triggers cell cycle arrest. However, cells undergoing transformation in intraepithelial lesions actively proliferate. To prove that the different expression patterns of p16(INK4a) , i.e., focal versus diffuse, reflect biologically different entities, we hypothesized that p16(INK4a) -positive cells in epithelia displaying focal p16(INK4a) expression pattern do not coexpress proliferation-associated Ki-67 protein, while p16(INK4a) -positive cells in lesions with diffuse p16(INK4a) expression may do. A total of 138 cervical cone biopsies were stained for the expression of p16(INK4a) and Ki-67 using a primary antibody cocktail. All metaplastic lesions (n = 21) displayed focal staining for p16(INK4a) , and in all of these lesions p16(INK4a) -positive cells were found to be negative for Ki-67 expression. Diffuse expression of p16(INK4a) was observed in 12/21 (57.1%) cervical intraepithelial neoplasia (CIN) 1 lesions, all of them simultaneously showed Ki-67 immunoreactivity in a large proportion of p16(INK4a) -positive cells. Seventeen of 23 (73.9%) CIN2 lesions and all 27 (100%) CIN3/carcinoma in situ (CIS) as well as all 46 (100%) carcinoma cases displayed diffuse and combined expression of p16(INK4a) and Ki-67. Coexpression of Ki-67 and p16(INK4a) in the same cell is entirely restricted to cervical lesions displaying diffuse p16(INK4a) expression, whereas in lesions with focal p16(INK4a) expression, p16(INK4a) -expressing cells are negative for Ki-67. Thus, diffuse expression of p16(INK4a) reflects lesions with proliferation-competent cells, while p16(INK4a) -expressing cells associated with focal expression patterns are cell cycle arrested.
宫颈上皮基底层和副基底层细胞中 p16(INK4a)的弥漫性过表达是 HPV 介导的转化的标志。非发育不良的上皮中偶尔会观察到局灶性 p16(INK4a)表达。在正常细胞中，p16(INK4a)的表达会引发细胞周期停滞。然而，上皮内病变中发生转化的细胞会积极增殖。为了证明 p16(INK4a)的不同表达模式，即局灶性与弥漫性，反映了生物学上不同的实体，我们假设显示局灶性 p16(INK4a)表达模式的上皮中的 p16(INK4a)阳性细胞不会共表达增殖相关的 Ki-67 蛋白，而弥漫性 p16(INK4a)表达的病变中的 p16(INK4a)阳性细胞可能会。总共对 138 例宫颈锥切活检进行了 p16(INK4a)和 Ki-67 的表达染色，使用了一组主要抗体混合物。所有的化生病变（n = 21）均显示局灶性 p16(INK4a)染色，在所有这些病变中，p16(INK4a)阳性细胞均未表达 Ki-67。12/21（57.1%）的宫颈上皮内瘤变（CIN）1 病变中观察到弥漫性 p16(INK4a)表达，其中所有病变均同时在大量 p16(INK4a)阳性细胞中显示 Ki-67 免疫反应性。17/23（73.9%）的 CIN2 病变和所有 27（100%）的 CIN3/原位癌（CIS）以及所有 46（100%）的癌病变均显示弥漫性和联合表达 p16(INK4a)和 Ki-67。Ki-67 和 p16(INK4a)在同一细胞中的共表达完全限于显示弥漫性 p16(INK4a)表达的宫颈病变，而在局灶性 p16(INK4a)表达的病变中，p16(INK4a)表达细胞 Ki-67 阴性。因此，弥漫性 p16(INK4a)的表达反映了具有增殖能力的细胞的病变，而与局灶性表达模式相关的 p16(INK4a)表达细胞处于细胞周期停滞状态。
