Role of the insulin/IGF-axis in incident CIN-2+

描述（由申请人提供）：胰岛素/胰岛素样生长因子（IGF）轴是细胞增殖/存活的主要调节因子，循环IGF轴蛋白水平与几种实体瘤（包括乳腺和前列腺肿瘤）的风险相关。然而，关于IGF-轴与宫颈癌的关系知之甚少，宫颈癌是全球女性第二大常见癌症。据我们所知，唯一的前瞻性数据来自我们的小型试点调查。该研究发现IGF轴蛋白水平与致癌性人乳头瘤病毒（HPV）的持续存在以及致癌性HPV+宫颈病变相关。不过，这些病变几乎都是低级别的。在进行更全面、更昂贵的研究（例如，用配对的血清/组织和重复测试）进行。简言之，IGF-I是具有促有丝分裂/抗凋亡活性的激素，并且大多数细胞表达IGF-I受体。IGF-I受体的下调甚至可以逆转宫颈癌细胞系的转化表型。相反，IGF结合蛋白（IGFBP）-3，最丰富的IGFBP，具有直接（IGF-I独立）和间接（隔离IGF-I）抗有丝分裂/促凋亡作用。尽管如此，IGF轴和HPV/宫颈瘤变的人体研究很少，并且先前的数据（所有横断面）不一致。因此，如上所述，我们在137名女性中进行了一项关于IGF轴和HPV自然史的小型前瞻性初步研究。致癌HPV的持续存在与IGF-I/IGFBP-3比值增加相关（HR= 7.1;1.8-25），而IGFBP-3增加与致癌HPV+宫颈瘤变的低风险相关（HR=0.07; 0.01-0.66）。我们还注意到，在一些研究中，肥胖与宫颈癌的风险有关。我们假设这种关系是由于肥胖妇女中高胰岛素血症的流行，因为胰岛素与IGF-I具有氨基酸序列同源性，以及促有丝分裂/抗凋亡活性。如果正确的话，胰岛素/IGF轴可能被用于宫颈癌的治疗，而且，在宫颈癌筛查。为了研究宫颈肿瘤发生中的胰岛素/IGF轴，我们提出了一项病例队列研究，该研究是由NCI/NIH建立的少数几个大型的、真正基于人群的宫颈疾病队列研究之一，称为Guanacaste项目（GP）（N= 7，278）。具体而言，我们将在N=182名患有持续致癌HPV的GP女性和N=142名患有宫颈癌前病变的GP女性（即，CIN-2或更差）。基线时选择的随机子队列（N=900）将用作对照组。这些累积数据将用于实现三个目标：确定IGF-I、IGF-II、IGFBP-3和C肽与（i）致癌HPV持续存在和（ii）宫颈癌前病变的关系。（我们的主要终点），以及（iii）研究哥斯达黎加妇女的胰岛素/IGF轴水平及其相关因素，使用来自子队列的数据（因为发达国家以外的胰岛素/IGF轴数据稀少）。 公共卫生相关性：胰岛素/胰岛素样生长因子（IGF）轴是细胞增殖/存活的主要调节因子，循环IGF轴蛋白水平与几种实体瘤（包括乳腺癌和前列腺癌）的风险相关。然而，关于IGF-轴与宫颈癌的关系知之甚少，宫颈癌是全球女性第二大常见癌症。本申请提出了胰岛素/IGF轴水平及其与宫颈癌前病变（即，宫颈上皮内瘤变[CIN]-2或更差）。如果证实胰岛素/IGF-轴在宫颈肿瘤发生中起重要作用，那么胰岛素/IGF-轴及其信号通路可能被用于宫颈癌治疗，此外，还可以用于加强筛查实践以预防宫颈癌。

DESCRIPTION (provided by applicant): The insulin/insulin-like growth factor (IGF)-axis is a major regulator of cell proliferation/survival, and circulating IGF-axis protein levels are associated with the risk of several solid tumors, including tumors of the breast and prostate. Little is known, however, regarding the IGF-axis's relation with cervical cancer, the second most common cancer in women worldwide. To our knowledge, the only prospective data come from our small pilot investigation. That study found associations of IGF-axis protein levels with persistence of oncogenic human papillomavirus (HPV), and with oncogenic HPV+ cervical lesions. Those lesions, though, were almost all low grade. A study that demonstrates a relationship between IGF-axis levels and incident cervical pre-cancer (CIN- 2+) is needed before more comprehensive, costly studies (e.g., with paired serum/tissue and repeated testing) are conducted. Briefly, IGF-I is a hormone with mitogenic/anti-apoptotic activity, and most cells express the IGF-I receptor. Down-regulation of the IGF-I receptor can even reverse the transformed phenotype of cervical cancer cell lines. In contrast, IGF binding protein (IGFBP)-3, the most abundant IGFBP, has both direct (IGF-I independent) and indirect (sequestering IGF-I) anti-mitotic/pro-apoptotic effects. Nonetheless, there have been few human studies of the IGF-axis and HPV/cervical neoplasia, and the prior data (all cross-sectional) were inconsistent. Therefore, as above, we conducted a small prospective pilot study of the IGF-axis and HPV natural history in 137 women. Persistence of oncogenic HPV was associated with increasing IGF-I/IGFBP-3 ratio (HR= 7.1;1.8-25), while increasing IGFBP-3 was associated with low risk of oncogenic HPV+ cervical neoplasia (HR=0.07; 0.01-0.66). We also note that obesity has been associated with risk of cervical cancer in some studies. We hypothesize that this relationship is due to the prevalence of hyperinsulinemia in obese women, since insulin has amino acid sequence homology, as well as mitogenic/anti-apoptotic activity, in common with IGF-I. If correct, the insulin/IGF-axis might be exploited in the treatment of cervical cancer and, moreover, in cervical cancer screening. To study the insulin/IGF-axis in cervical tumorigenesis we propose a case-cohort study set in one of the few large, truly population-based cohort investigations of cervical disease, called the Guanacaste Project (GP) (N=7,278), established by NCI/NIH. Specifically, we will measure baseline serum levels of IGF-I, IGF-II, IGFBP-3, and C-peptide (a surrogate marker of insulin that does not require fasting blood), in N=182 GP women with persistent oncogenic HPV, and N=142 with incident cervical pre-cancer (i.e., CIN-2 or worse). A random subcohort selected at baseline (N=900) will be used as the comparison group. These cumulative data will then be used to address three Aims: To determine the associations of IGF-I, IGF-II, IGFBP-3, and C- peptide with (i) persistence of oncogenic HPV, and (ii) with cervical pre-cancer (our major endpoint), as well as (iii) to study insulin/IGF-axis levels and the factors associated with them in Costa Rican women, using data from the subcohort (since there is sparse insulin/IGF-axis data outside of developed countries). PUBLIC HEALTH RELEVANCE: The insulin/insulin-like growth factor (IGF)-axis is a major regulator of cell proliferation/survival, and circulating IGF-axis protein levels are associated with the risk of several solid tumors, including tumors of the breast and prostate. Little is known, however, regarding the IGF-axis's relation with cervical cancer, the second most common cancer in women worldwide. This application proposes the first prospective study of insulin/IGF-axis levels and their associations with incident cervical pre-cancer (i.e., cervical intraepithelial neoplasia [CIN]-2 or worse). If it is confirmed that the insulin/IGF-axis plays an important role in cervical tumorigenesis then the insulin/IGF-axis and its signaling pathways might be exploited in cervical cancer treatment and, moreover, in enhancing screening practices to prevent cervical cancer.