Interaction of HPV with cells of the transformation zone

描述（由申请人提供）：感染高危人乳头瘤病毒（HPV）的一个子集是宫颈癌的主要危险因素。HPV-16 E6和E7基因在大多数宫颈癌中选择性保留和表达，HPV的持续感染和宫颈细胞的永生化是宫颈癌发生的重要早期事件。虽然感染HPV是恶性进展所必需的，但这还不够。大多数高危HPV感染被宿主的免疫反应识别和消除；只有一小部分发展为浸润性宫颈癌。我们对两个重要问题感兴趣：(1)进展中的感染有什么独特之处；(2)在hpv感染细胞中促进宫颈癌发生的关键辅助因素是什么。虽然HPV感染发生在整个子宫颈，但大约90%的宫颈癌发生在一个小的解剖区域，即转化区。转化区由子宫颈外层状鳞状上皮和子宫颈内柱状分泌上皮之间的狭长带状化生鳞状上皮组成。几乎所有的宫颈癌都起源于转化区，但目前尚不清楚为什么来自该区域的hpv感染细胞有如此高的进展可能性。我们假设来自转化区的细胞比来自周围外阴和宫颈内的细胞更容易被HPV-16永生化。我们还预测，来自转化区的hpv -16永生化细胞在促进宫颈癌发生的两种辅助因子——慢性炎症和雌激素的作用下，最容易发生增殖和发育不良分化。为了检验这些问题，将从转化区、宫颈外和宫颈内培养人上皮细胞。将比较培养的细胞对HPV-16永生化的易感性，并研究导致永生化频率差异的潜在机制。还将评估来自每个解剖区域的hpv永生化上皮细胞对两种辅助因子的反应，这两种辅助因子是雌激素和促炎细胞因子肿瘤坏死因子- α （TNF-¿）。由于大多数宫颈癌起源于转化区，因此关注这些细胞如何与HPV相互作用是合乎逻辑的。如果我们的实验成功，我们的结果可能有助于识别重要的信号通路或转化区细胞特有的生物标志物，并且可以用于改进筛选，预防或治疗。

DESCRIPTION (provided by applicant): Infection with a subset of high-risk human papillomaviruses (HPV) is the major risk factor for cervical cancer. The HPV-16 E6 and E7 genes are selectively retained and expressed in most cervical carcinomas, and persistent infection with HPV and immortalization of cervical cells are important early events in cervical carcinogenesis. Although infection with HPV is required for malignant progression, it is not sufficient. Most high-risk HPV infections are recognized and eliminated by the host's immune response; only a small subset progress to invasive cervical cancer. We are interested in two important questions: (1) what is unique about infections that progress and (2) what are the critical cofactors that promote cervical carcinogenesis in HPV-infected cells. Although HPV infections occur throughout the cervix, approximately 90% of cervical cancers occur within a small anatomic region known as the transformation zone. The transformation zone consists of a narrow band of metaplastic squamous epithelium between the stratified squamous epithelium of the ectocervix and the columnar secretory epithelium of the endocervix. Almost all cervical cancers originate within the transformation zone, but it is unclear why HPV-infected cells from this region have such a high probability of progression. We hypothesize that cells from the transformation zone are more susceptible to immortalization by HPV-16 than cells from the surrounding ecto and endocervix. We also predict that HPV-16-immortalized cells derived from transformation zone are most susceptible to proliferation and dysplastic differentiation in response to two cofactors that promote cervical carcinogenesis, chronic inflammation and estrogen. To examine these questions, human epithelial cells will be cultured from the transformation zone, ectocervix, and endocervix. The cultured cells will be compared for susceptibility to immortalization by HPV-16, and potential mechanisms that contribute to differences in immortalization frequency will be examined. HPV-immortalized epithelial cells from each anatomic region will also be assessed for their response to two cofactors that contribute to cervical cancer, estrogen and the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-¿). Because most cervical cancers arise from the transformation zone, it is logical to focus on how these cells interact with HPV. If our experiments are successful, our results may help to identify important signal pathways or biomarkers that are unique to transformation zone cells and that can be targeted for improved screening, prevention or therapy.