Ishikawa M, Fujii T, Saito M, Nindl I, Ono A, Kubushiro K, Tsukazaki K, Mukai M, Nozawa S
Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Int J Gynecol Cancer. 2006 Jan-Feb;16(1):347-53. doi: 10.1111/j.1525-1438.2006.00355.x.
Overexpression of p16(INK4a) has been observed when retinoblastoma protein is inactivated by high-risk human papillomavirus (HPV) oncoprotein E7. We investigated overexpression of p16(INK4a) and HPV infection in cervical squamous neoplasia to evaluate the oncogenic potential among various HPV subtypes. The high-risk HPV was detected by PCR in 69.8% (37/53), 97.5% (39/40), 91.7% (44/48), and 100% (16/16) of cervical intraepithelial neoplasia (CIN)1, CIN2, CIN3, and squamous cell carcinoma (SCC), respectively. The p16(INK4a) overexpression was investigated immunohistochemically using a p16(INK4a)-specific monoclonal antibody (clone E6H4). In high-risk HPV positive cases, 32.4% (12/37) of CIN1, 82.1% (32/39) of CIN2, 93.2% (41/44) of CIN3, and all (16/16) SCC showed p16(INK4a) overexpression. The incidence of p16(INK4a) overexpression was significantly different between CIN1 and CIN2, suggesting that the disorder of cell cycle regulation by HPV frequently occurred from CIN2. As for CIN1 cases, p16(INK4a) overexpression was observed more frequently in HPV16 and HPV52 than in HPV51 and HPV35. Using p16(INK4a) as a bio marker of HPV oncogenic activity, we demonstrate that the level of pRb dysfunction by high-risk HPV varied from subtypes and was getting more frequent from CIN2.
当视网膜母细胞瘤蛋白被高危型人乳头瘤病毒（HPV）癌蛋白E7失活时，已观察到p16（INK4a）的过表达。我们研究了宫颈鳞状上皮瘤变中p16（INK4a）的过表达和HPV感染情况，以评估不同HPV亚型的致癌潜能。通过聚合酶链反应（PCR）检测到高危型HPV在宫颈上皮内瘤变（CIN）1、CIN2、CIN3和鳞状细胞癌（SCC）中的检出率分别为69.8%（37/53）、97.5%（39/40）、91.7%（44/48）和100%（16/16）。使用p16（INK4a）特异性单克隆抗体（克隆E6H4）通过免疫组织化学研究p16（INK4a）的过表达情况。在高危型HPV阳性病例中，CIN1的32.4%（12/37）、CIN2的82.1%（32/39）、CIN3的93.2%（41/44）以及所有SCC（16/16）均显示p16（INK4a）过表达。CIN1和CIN2之间p16（INK4a）过表达的发生率存在显著差异，这表明HPV导致的细胞周期调控紊乱通常从CIN2开始出现。对于CIN1病例，与HPV51和HPV35相比，HPV16和HPV52中p16（INK4a）过表达更为常见。使用p16（INK4a）作为HPV致癌活性的生物标志物，我们证明高危型HPV导致的视网膜母细胞瘤蛋白（pRb）功能障碍水平因亚型而异，且从CIN2开始更为频繁。
