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

描述(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，循环中的IGF轴蛋白水平与几种实体肿瘤的风险有关，包括乳腺癌和前列腺癌。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常见的癌症。据我们所知，唯一的预期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+宫颈病变之间存在关联。然而，这些损伤几乎都是低级别的。在进行更全面、更昂贵的研究(例如，配对血清/组织和重复检测)之前，需要进行一项研究，证明IGF轴水平与宫颈癌前病变(CIN-2+)之间的关系。简而言之，IGF-I是一种具有促分裂/抗凋亡活性的激素，大多数细胞都表达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，胰岛素样生长因子结合蛋白(IGFBP)-3是最丰富的IGFBP，具有直接(IGF-I非依赖性)和间接(隔离IGF-I)抗有丝分裂/促凋亡作用。然而，很少有关于IGF轴和HPV/宫颈肿瘤的人体研究，而且先前的数据(都是横断面的)是不一致的。因此，如上所述，我们对137名女性进行了一项关于IGF轴和HPV自然病史的小型前瞻性先导性研究。HPV的持续存在与IGF-I/IGFBP-3比值升高(HR=7.1；1.8~25)有关，而IGFBP-3升高与HPV+宫颈肿瘤的低风险相关(HR=0.07；0.01~0.66)。我们还注意到，在一些研究中，肥胖与患宫颈癌的风险有关。我们推测，这种关系是由于肥胖女性中普遍存在的高胰岛素血症，因为胰岛素具有与IGF-I相同的氨基酸序列同源性以及促有丝分裂/抗凋亡活性。如果正确，胰岛素/胰岛素样生长因子-轴可能被用于宫颈癌的治疗，甚至用于宫颈癌的筛查。为了研究胰岛素/胰岛素样生长因子轴在宫颈肿瘤发生中的作用，我们提出了一项病例队列研究，该研究是由NCI/NIH建立的为数不多的大型、真正基于人群的宫颈疾病队列调查之一，称为瓜纳卡斯特计划(GP)(N=7,278)。具体地说，我们将测量N=182名患有持续性致癌HPV的GP妇女和N=142名宫颈癌前病变(即CIN-2或更严重)患者的基线血清IGF-I、IGF-II、IGFBP-3和C肽(一种不需要空腹血液的胰岛素替代标记物)水平。在基线(N=900)处随机选择一个子队列作为对照组。这些累积数据将被用来解决三个目标：确定IGF-I、IGF-II、IGFBP-3和C-肽与(I)致癌HPV的持久性，以及(Ii)与宫颈癌前病变(我们的主要终点)的相关性，以及(Iii)使用来自次队列的数据研究哥斯达黎加妇女的胰岛素/IGF轴水平及其相关因素(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，循环中的IGF轴蛋白水平与几种实体肿瘤的风险有关，包括乳腺癌和前列腺癌。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常见的癌症。这项应用首次提出了胰岛素/IGF轴水平及其与宫颈癌前病变(即宫颈上皮内瘤变[CIN]-2或更严重)的相关性的前瞻性研究。如果证实胰岛素/IGF轴在宫颈肿瘤的发生中起重要作用，那么胰岛素/IGF轴及其信号通路可能被用于宫颈癌的治疗，并进一步加强宫颈癌的筛查工作。

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.