MODULATION OF HOST CELL APOPTOTIC RESPONSES BY HPVE7

描述（由申请人提供）：高危人类乳头瘤病毒（hpv）是宫颈癌的病原，是全球妇女癌症死亡的第二大常见原因。此外，高危hpv还与许多其他肛门生殖道癌有关，包括肛门癌、外阴癌和阴茎癌，以及大约20%的口腔癌。尽管最近引入了一种预防性疫苗，以防止感染某些高危型人乳头瘤病毒，但要想影响宫颈癌的发病率和死亡率，还需要几十年的时间。目前，仅在美国，每天就有10名女性死于宫颈癌。HPV相关癌变是由HPV E6/E7癌蛋白表达驱动的；这些蛋白不仅有助于诱导癌前病变，而且在机制上也有助于恶性进展，这是一种相对罕见的事件，通常发生在最初感染后的几年到几十年。进展通常与HPV基因组整合到宿主细胞染色体有关，这是病毒生命周期的最终事件。因此，E6和E7是唯一在宫颈癌中持续表达的病毒蛋白。该项目的重点是研究高危HPV癌蛋白的生物活性，并确定它们是否可以作为一种新的治疗方式来治疗高危HPV相关病变和癌症。在目的1中，我们提出确定hpv16e7诱导的人角化细胞营养前哨信号传导的机制基础，角化细胞是一种细胞肿瘤抑制途径，可以阻止发生致癌改变的细胞增殖，从而导致细胞异常增殖。目的2是确定hpv16e7诱导人角化细胞自噬的机制基础，以及这是否/如何与营养前哨信号传导相关联。由于自噬是一种古老而保守的代谢应激反应，我们将确定hpv16e7表达如何导致代谢需求增加。目的3是探讨hpv16e6消除hpv16e7诱导的营养前哨信号的机制。在这个目标中，我们将测试E6和E7可能靶向的途径的小分子抑制剂，以及目前在临床中的小分子抑制剂是否可以作为hpv相关病变和癌症的新治疗方式。由于E6和E7癌蛋白靶向的细胞通路在非hpv相关的人类实体瘤中经常因突变而功能失调，因此这些研究也可能适用于其他人类癌症的治疗。

DESCRIPTION (provided by applicant): 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.