Overexpression of p16 and p14ARF is associated with human papillomavirus infection in cervical squamous cell carcinoma and dysplasia
Overexpression of p16 and p14ARF is associated with human papillomavirus infection in cervical squamous cell carcinoma and dysplasia
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DOI：
10.1046/j.1440-1827.2002.01359.x
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发表时间：
2002-05-01
影响因子：
2.2
通讯作者：
Nakajima, T
中科院分区：
文献类型：
--
作者：
Sano, T;Masuda, N;Nakajima, T
CDKN2基因编码两种结构不同的蛋白质：周期蛋白依赖的激酶抑制因子p16，它调节视网膜母细胞瘤蛋白(PRB)依赖的G1期停滞；细胞周期抑制因子p14ARF，它阻断MDM2诱导的P53降解，导致P53水平增加，导致细胞周期停滞。最近的研究表明，p16和p14ARF的表达明显受pRb和p53状态的影响，p16在宫颈肿瘤中的过度表达是由于人乳头瘤病毒(HPV)E7蛋白对pRb的功能失活所致。为探讨p14ARF在宫颈鳞癌发生中的作用及其与其他细胞周期分子的关系，应用免疫组织化学方法对65例宫颈及生殖器尖锐湿疣和肿瘤组织中p16、p14ARF、P53和MDM2进行了检测，其中包括9例HPV阴性肿瘤。在大多数高危和中危HPV感染的宫颈癌和癌前病变中，p14ARF和p16蛋白明显过表达(即点状核免疫染色)。除1例和HPV感染风险较低的低度异型增生外，所有尖锐湿疣p14ARF免疫组织化学染色均为阴性，在非肿瘤性细胞和间充质细胞中也可见表达。我们的结果清楚地表明，在HPV相关的宫颈癌细胞中，p14ARF的过度表达模式与在其他器官的癌症中不同，p14ARF的过度表达可能是由于HPV癌蛋白对pRB和P53蛋白功能失活的负反馈结果。
The CDKN2 gene encodes two structurally different proteins: a cyclin-dependent kinase inhibitor, p16, which regulates retinoblastoma protein (pRb)-dependent G1 arrest, and a cell cycle inhibitor, p14ARF, which blocks MDM2-induced p53 degradation resulting in an increase in p53 levels that leads to cell cycle arrest. Recent studies have revealed that expression of p16 and p14ARF is influenced markedly by the status of pRb and p53, and p16 overexpression has been demonstrated in cervical neoplasia because of functional inactivation of pRb by the human papillomavirus (HPV) E7 protein. To clarify the p14ARF status and the relationship between p16/p14ARF and other cell cycle molecules in cervical carcinogenesis, immunohistochemical analysis of p16, p14ARF, p53 and MDM2 was performed on 65 samples of cervical and genital condylomatous and neoplastic lesions, including nine HPV-negative tumors. In most cervical cancers and preneoplastic lesions with HPV infection of high and intermediate risk, a marked overexpression of p14ARF as well as the p16 protein (i.e. dotted nuclear immunostaining) was observed. All condyloma acuminata except one and low-grade dysplasia with HPV infection of low risk, such as HPV 6, immunohistochemically showed completely negative staining for p14ARF, also seen in non-neoplastic and mesenchymal cells. Our results clearly show that the mode of p14ARF overexpression in cervical neoplastic cells with HPV association differs from that in cancers of other organs without HPV association, and the p14ARF overexpression may be attributable to a negative feedback result in the functional inactivation of the pRb and p53 proteins by HPV oncoproteins.