Etiology of cervical cancer health disparity in American Indian women

描述(申请人提供)：宫颈癌是全球第二大最常见的癌症，也是女性癌症相关死亡的第二大原因。居住在北部平原的美国印第安人(AI)妇女患宫颈癌的几率更高，死亡率也更高。我们最近的研究表明，人工智能女性的HPV感染发生率是HPV感染女性的两倍多，HPV阳性的人工智能女性进行异常PAP检测的可能性是HPV阳性高加索女性的两倍；这表明导致HPV病理的潜在原因。一个潜在的辅助因素可能是烟雾暴露及其对宿主免疫反应和HPV致癌的影响。我们的数据表明，人工智能女性吸烟的人数是高加索女性的4倍，而且大多数HPV阳性的人工智能女性吸烟。虽然吸烟是公认的宫颈癌风险因素，但HPV和烟雾化合物之间的分子相互作用尚不清楚。我们的实验室最近发现，吸烟致癌物质苯并[a]芘(BaP)会增加HPV癌蛋白的表达，这表明HPV感染与吸烟之间存在直接的分子联系。我们还发现，姜黄素是一种天然的抗癌化合物，可以有效地抑制HPV癌蛋白的表达。基于这一令人信服的证据，我们假设暴露在烟草烟雾中与HPV感染协同作用，并通过增加HPV癌蛋白(E6/E7)的表达和调节细胞/体液免疫反应而增加美国印第安人妇女宫颈癌的发病率和严重程度。此外，我们假设姜黄素或纳米姜黄素可能是抑制AI女性HPV感染的有效方法。我们建议1)研究HPV感染、BaP与宫颈癌发生发展之间协同作用的新机制，2)评价姜黄素/纳米姜黄素在临床前和临床环境中抑制HPV癌基因表达的有效性，以及3)研究吸烟暴露对宫颈免疫反应的影响。这项研究的结果将提供有关导致人工智能女性宫颈癌健康差异的潜在病因的信息，并最终将减轻宫颈癌的负担。

DESCRIPTION (provided by applicant): Cervical cancer is the second most frequently diagnosed cancer and the second leading cause of cancer related deaths in women worldwide. American Indian (AI) women living on the Northern Plains have a greater incidence of cervical cancer and suffer from a higher mortality rate. Our recent studies have shown that AI women have more than twice the incidence of HPV infection and that HPV positive AI women have a two times higher likelihood of having abnormal PAP tests than HPV positive Caucasian women; suggesting underlying causes which increase HPV pathology. One potential cofactor may be smoke exposure and its effects on the host immune response and HPV oncogenesis. Our data indicate that 4 times more AI women smoke as compared to Caucasian women and the majority of HPV positive AI women smoke. While smoking is a recognized risk factor for cervical cancer, the molecular interactions between HPV and smoke compounds are unknown. Our laboratory has recently shown that smoke carcinogen Benzo[a]Pyrene (BaP) increases the expression of HPV oncoproteins, suggesting a direct molecular link between HPV infection and exposure to smoke. We have also identified that curcumin, a natural anti-cancer compound, effectively inhibits the expression of HPV oncoproteins. Based on this compelling evidence, we hypothesize that exposure to tobacco smoke synergizes with HPV infection and increases the incidence and severity of cervical cancer in American Indian women by increasing the expression of HPV oncoproteins (E6/E7) and modulating cellular/humoral immune responses. Additionally, we hypothesize that curcumin or nanocurcumin may be effective methods for the repression of HPV infection in AI women. We propose to 1) investigate novel mechanisms of synergy between HPV infection, BaP and the development of cervical cancer, 2) evaluate the efficacy of curcumin/nanocurcumin to suppress HPV oncogene expression in preclinical and clinical settings, and 3) to investigate the effect of smoke exposure on cervical immune responses. The results of this study will provide information regarding underlying etiological factors that are responsible for cervical cancer health disparity in AI women and will ultimately reduce the burden of cervical cancer.