Pillai M R, Nair M K
Division of Laboratory Medicine, Regional Cancer Centre, Thiruvananthapuram. India.
Exp Mol Pathol. 2000 Dec;69(3):233-41. doi: 10.1006/exmp.2000.2335.
High-risk human papillomaviruses (HPVs) have been shown to be involved in the pathogenesis of many squamous carcinomas, particularly those of the uterine cervix. A number of random studies have also reported association of high-risk HPV subtypes with cancers of the oral cavity, larynx, hypopharynx, and esophagus. The roles of other molecular factors involved during HPV infection in these tumors still remain unclear. Recent findings from our laboratories have suggested possible mechanisms associated with HPV-mediated carcinogenesis. Both p53 mutation-dependent and mutation-independent pathways may be associated with HPV-mediated carcinogenesis, the former mainly in upper aerodigestive tract tumors (UADT) and the latter in cervical tumors. In cervical tumors, inactivation of the p53 tumor suppressor protein by the E6 gene product of high-risk HPVs and mutation of the p53 gene in UADT is associated with alterations in the apoptotic regulatory bcl-2 and bax genes, leading to downregulation of programmed cell death (PCD) and increased cell proliferation. HPV infection is also associated with increased tissue angiogenesis and activation of telomerase. Altered kinetics of telomere fragments is evident in HPV-infected tissue. We therefore believe that the combined manifestations of all these factors may contribute to development of a "condemned mucosa syndrome" facilitating development UADT and cervical cancers. A distinct step in the pathogenesis of both types of tumors may only be in the mode of p53 inactivation, whereas all other events appear to be strongly correlated to the presence of HPV. The development and validation of such a molecular model has significant clinical priority. It can be used to identify target populations or individuals for intervention, to monitor effects of intervention, and to determine which individuals or groups are at increased risk of developing cancer.
高危型人乳头瘤病毒（HPV）已被证明与许多鳞状细胞癌的发病机制有关，尤其是子宫颈癌。一些随机研究还报告了高危型HPV亚型与口腔、喉、下咽和食管癌的关联。HPV感染过程中涉及的其他分子因素在这些肿瘤中的作用仍不清楚。我们实验室最近的研究结果表明了与HPV介导的致癌作用相关的可能机制。p53突变依赖性和非依赖性途径都可能与HPV介导的致癌作用有关，前者主要在上呼吸消化道肿瘤（UADT）中，后者在宫颈肿瘤中。在宫颈肿瘤中，高危型HPV的E6基因产物使p53肿瘤抑制蛋白失活，而在UADT中p53基因的突变与凋亡调节基因bcl-2和bax的改变有关，导致程序性细胞死亡（PCD）下调和细胞增殖增加。HPV感染还与组织血管生成增加和端粒酶激活有关。在HPV感染的组织中，端粒片段的动力学改变很明显。因此，我们认为所有这些因素的综合表现可能导致“受谴责的黏膜综合征”的发展，促进UADT和宫颈癌的发生。这两种肿瘤发病机制中的一个明显步骤可能仅在于p53失活的模式，而所有其他事件似乎都与HPV的存在密切相关。这种分子模型的开发和验证具有重要的临床意义。它可用于识别干预的目标人群或个体，监测干预效果，并确定哪些个体或群体患癌风险增加。
