MODULATION OF HOST CELL APOPTOTIC RESPONSES BY HPVE7

项目摘要 高危型人乳头瘤病毒（HPV）是宫颈癌的病原体， 全球女性癌症死亡的原因。此外，高危HPV还与许多 其他肛门生殖道癌，包括肛门、外阴和阴茎癌以及约20%的 口腔癌尽管最近引入了预防性疫苗，以防止感染 一些高危HPV类型，这将是几十年前，这将影响宫颈癌的发病率和死亡 rates.目前，仅在美国，每天就有10名妇女死于宫颈癌。hpv相关 致癌作用由HPV E6/E7癌蛋白表达驱动;这些蛋白不仅有助于诱导 癌前病变，但也机械地有助于恶性进展，一个相对罕见的事件 通常发生在初次感染后数年至数十年。进展常常与 HPV基因组整合到宿主细胞染色体中，这是病毒生命周期的终末事件。作为 因此，E6和E7是唯一在宫颈癌中持续表达的病毒蛋白。这 该项目的重点是调查高危HPV癌蛋白的生物学活性，并确定是否 它们可以作为一种新的治疗方式用于高危HPV相关病变和癌症。在 目的1，拟确定HPV 16 E7诱导的营养性前哨信号转导的机制基础， 人角质形成细胞，一种细胞肿瘤抑制途径，可阻止具有以下特征的细胞增殖： 患有致癌性改变，导致细胞异常增殖。目的2是确定 HPV 16 E7诱导人角质形成细胞自噬的基础及其是否与营养性前哨因子有关 发信号。由于自噬是一种进化上古老而保守的代谢应激反应， 确定HPV 16 E7表达如何导致代谢需求增加。目的3是研究 HPV 16 E6消除HPV 16 E7诱导的营养性前哨信号传导的机制。为此，我们将 测试E6和E7可能靶向的途径的小分子抑制剂，以及目前 在临床上可以作为HPV相关病变和癌症的新治疗方式。以来 由E6和E7癌蛋白靶向的细胞通路经常由于以下原因而功能失调： 这些研究也可适用于治疗非HPV相关的人实体瘤中的其他HPV突变。 人类癌症

Project Summary High-risk human papillomaviruses (HPVs) are etiological agents of cervical cancer, the second most common cause of cancer death in women worldwide. In addition, high-risk HPVs are also associated with a number of other anogenital tract carcinomas, including, anal, vulvar and penile cancers as well as approximately 20% of oral cancers. Despite the recent introduction of a prophylactic vaccine that is to protect from infection with some high-risk HPV types, it will be several decades before this will affect cervical cancer incidence and death rates. Currently 10 women succumb to cervical cancer every day in the US, alone. HPV-associated carcinogenesis is driven by HPV E6/E7 oncoprotein expression; these proteins not only contribute to induction of premalignant lesions, but also mechanistically contribute to malignant progression, a relatively rare event that generally occurs several years to decades after the initial infection. Progression is frequently associated with HPV genome integration into a host cellular chromosome, a terminal event for the viral life cycle. As a consequence, E6 and E7 are the only viral proteins that are consistently expressed in cervical cancers. This project is focused on investigating biological activities of high-risk HPV oncoproteins and to determine whether they could be harnessed as a novel therapeutic modality for high-risk HPV-associated lesions and cancers. In aim 1, it is proposed to determine the mechanistic basis of HPV16 E7-induced trophic sentinel signaling in human keratinocytes, a cellular tumor suppressor pathway that thwarts the proliferation of cells that have suffered oncogenic alterations, which lead to aberrant cell proliferation. Aim 2 is to determine the mechanistic basis of HPV16 E7-induced autophagy in human keratinocytes and if/how this is connected to trophic sentinel signaling. Since autophagy is an evolutionary ancient and conserved response to metabolic stress we will determine how HPV16 E7 expression causes increased metabolic requirements. Aim 3 is to investigate the mechanism by which HPV16 E6 abrogates HPV16 E7 induced trophic sentinel signaling. In this aim we will test whether small molecule inhibitors of the pathways that E6 and E7 may be targeting and that are currently in the clinic may be harnessed as a novel therapeutic modality for HPV-associated lesions and cancers. Since the cellular pathways that are targeted by the E6 and E7 oncoproteins are frequently rendered dysfunctional by mutation in non-HPV associated human solid tumors, these studies may also be applicable for therapy of other human cancers.