The Role of HMG-I/Y in Uterine Cancer

描述(申请人提供)：子宫癌是最常见的女性生殖道癌症，在美国女性癌症死亡原因中排名第四。唯一可用的治疗方法是子宫切除术；这种疾病扩散到子宫外后，没有有效的辅助治疗方法。因此，进一步的研究有可能极大地有益于妇女的健康。尽管这种癌症的发病率很高，但导致子宫肿瘤转化的分子事件却知之甚少。此外，可用于研究这些癌症的动物模型有限。为了更好地了解子宫癌是如何发展的，我们正在研究与其发病机制有关的基因。我们的重点是HMG-I/Y基因，因为我们的初步研究表明，它在子宫癌的发生发展中发挥着重要作用。HMG-I/Y基因编码HMG-I和-Y染色质结合蛋白，其功能是调节基因表达。我们的初步研究表明，HMG-I的mRNA和蛋白在高度恶性的人类子宫癌中上调，但在低度恶性子宫癌、良性肿瘤或正常组织中不表达。我们还证明了HMG-I和-Y在培养细胞中具有致癌作用。我们最近培育出了在淋巴组织中过度表达HMG-I的转基因小鼠，所有小鼠都患上了侵袭性淋巴瘤。转基因基因也在子宫中过度表达，所有雌性小鼠都会患上子宫肿瘤，其病理类似于人类子宫腺肉瘤。因此，我们假设hMG-I是一个在人类子宫癌发病机制中起重要作用的癌基因。我们的总体目标是确定HMG-I在子宫癌中的作用，并开始利用我实验室开发的独特试剂探索转化机制。我们的具体目标是：1.)确定HMG-I/Y是否可以作为更具侵袭性的子宫癌的诊断标志物。2.)确定HMG-I/Y是否是子宫癌细胞转化所必需的。3.)利用基因表达谱分析开始确定H/WG-/-介导的子宫癌转化的分子途径。这些研究的结果将增强我们对子宫癌的理解，并最终将导致更好的治疗方法的发展。相关性：子宫癌是一种常见的、通常无法治愈的癌症，影响着全世界的女性。这种癌症扩散到子宫外后，没有有效的治疗方法。因此，迫切需要研究来确定这些癌症是如何发展的，以便设计更好的治疗方法。

DESCRIPTION (provided by applicant): Uterine cancer is the most common cancer of the female genital tract and the fourth most frequent cause for cancer death in women in the United States. The only available treatment is hysterectomy; there is no effective adjuvant therapy for this disease after it has spread outside the uterus. Thus, further study has the potential to significantly benefit women's health. Despite the high prevalence of this cancer, the molecular events that lead to neoplastic transformation in the uterus are poorly understood. In addition, there are limited animal models available to study these cancers. To better understand how uterine cancers develop, we are studying genes that contribute to its pathogenesis. Our focus is the HMG-I/Y gene because our preliminary studies suggest that it plays an important role in the development of uterine cancer. The HMG-I/Y gene encodes the HMG-I and - Y chromatin binding proteins, which function in regulating gene expression. Our pilot study shows that HMG-I mRNA and protein are up-regulated in high-grade human uterine cancers, but not low- grade cancers, benign tumors, or normal tissue. We also demonstrated that HMG-I and -Y have oncogenic properties in cultured cells. We recently generated transgenic mice that overexpress HMG-I in lymphoid tissue and all of them develop aggressive lymphoma. The transgene is also overexpressed in the uterus and all female mice develop uterine tumors with pathology resembling human uterine adenosarcoma. Thus, we hypothesize that HMG-I is an oncogene important in the pathogenesis of human uterine cancer. Our overall goal is to define the role of HMG-I in uterine cancer and begin to explore the mechanisms involved in transformation using unique reagents developed in my laboratory. Our Specific Aims are: 1.) Determine if HMG-I/Y can serve as a diagnostic marker for more aggressive uterine cancer. 2.) Determine if HMG-I/Y is necessary for transformation in uterine cancer cells. 3.) Begin to define the molecular pathways involved in H/WG-/-mediated transformation in uterine cancer using gene expression profile analysis. Results from these studies will enhance our understanding of uterine cancer and should ultimately lead to the development of better therapy. Relevance: Uterine cancer is a common and often incurable cancer that affects women worldwide. There is no effective therapy for this cancer after it has spread outside the uterus. Thus, research is urgently needed to determine how these cancers develop in order to design better therapies.