The Role of HMG-I/Y in Uterine Cancer

描述（由申请人提供）：子宫癌是女性生殖道最常见的癌症，也是美国女性癌症死亡的第四大常见原因。唯一可用的治疗方法是子宫切除术;当它扩散到子宫外后，没有有效的辅助治疗方法。因此，进一步的研究有可能大大有益于妇女的健康。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，我们正在研究有助于其发病机制的基因。我们的重点是HMG-I/Y基因，因为我们的初步研究表明，它在子宫癌的发展中起着重要作用。HMG-I/Y基因编码HMG-I和- Y染色质结合蛋白，其在调节基因表达中起作用。我们的初步研究表明，HMG-I mRNA和蛋白在高级别人类子宫癌中上调，但在低级别癌症、良性肿瘤或正常组织中不上调。我们还证明了HMG-I和-Y在培养细胞中具有致癌特性。我们最近产生了在淋巴组织中过表达HMG-I的转基因小鼠，并且它们都发展为侵袭性淋巴瘤。转基因也在子宫中过表达，所有雌性小鼠均发生子宫肿瘤，病理学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很重要的癌基因。我们的总体目标是确定HMG-I在子宫癌中的作用，并开始使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.）的情况。确定HMG-I/Y是否是子宫癌细胞转化所必需的。3.）第三章开始使用基因表达谱分析来确定H/WG-/-介导的子宫癌转化中涉及的分子途径。这些研究的结果将增强我们对子宫癌的理解，并最终导致更好的治疗方法的发展。相关性：子宫癌是一种常见的，往往是无法治愈的癌症，影响世界各地的妇女。这种癌症在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.