Role of Hsal 2 in Ovarian Cancer

描述(申请人提供)：马博士的总体目标是获得在人类癌症生物学领域从事研究的技能和知识，并成为该领域的独立内科科学家，这与他之前的经验有相当大的偏离。进行概述的实践和说教培训以及其他指导活动将是实现这一目标的关键。总体研究目标是阐明同源异型盒基因Hsal2在卵巢癌发生发展中的作用。确定这种侵袭性极强的癌症的潜在机制对于开发新的治疗方法和提高存活率至关重要。PI之前的研究证明了一种新的肿瘤抑制基因Hsal2，它与果蝇中的Sal同源盒基因同源，在大多数卵巢上皮癌细胞中发生了改变或缺失。该基因的重新表达抑制了卵巢癌细胞系的生长和DNA合成，并抑制了裸鼠体内的肿瘤形成。PI还证明了Hsal-2的转录调控由两个独立的启动子控制，并且在一些人类癌症中Hsal-2启动子的使用发生了改变。在小鼠中，Hsal 2能够与多瘤病毒的大T抗原结合，多瘤病毒是一种诱导多种肿瘤的病毒。他的研究提供了强有力的证据，证明Hsal2可能是卵巢癌的潜在肿瘤抑制基因。这些和其他观察结果导致假设，Hsal-2亚型可能在卵巢癌的发生和发展中发挥作用。为了验证这一点，两个特定的目标将研究Hsal2亚型的功能作用和潜在的表达机制。目的1通过研究Hsal2亚型过表达对肿瘤致瘤性的影响，找出从属于Hsal2异构体表达的靶基因，以及Hsal2亚型上游调控因子的特征，确定Hsal2异构体表达改变在卵巢癌发生发展中的作用。目的研究卵巢癌组织中Hsal2基因P1和P2启动子的作用，检测Hsal 2基因启动子中CpG岛的甲基化状态，并将其与卵巢癌组织中Hsal 2基因表达的相关性，探讨卵巢癌Hsal 2亚型表达改变的可能机制。这些研究将为深入了解hsal-2调控卵巢正常上皮细胞生长和分化的机制(S)提供依据。如果HSAL2的下调被证明激活了卵巢癌细胞中的某些致癌途径或抑制了肿瘤抑制基因途径(S)，就可以设计出针对这些途径的治疗药物。

DESCRIPTION (provided by applicant): Dr. Ma's overall goal is to acquire the skills and knowledge to pursue research in the field of human cancer biology and become an independent physician-scientist in this field, which is a considerable departure from his prior experience. Pursuing the outlined practical and didactic training and other mentored activities will be key toward achieving this end. The overall research goal is to elucidate the role of the homeobox gene Hsal 2 in ovarian cancer initiation and development. Determining the underlying mechanisms of this very aggressive cancer is critical for developing new therapies and improving survival. The PI's prior research demonstrated a new tumor suppressor gene, Hsal 2, homologous to the Sal homeobox gene in Drosophila, that is altered or missing in most ovarian epithelial cancer cells. Re-expression of this gene inhibits growth and DNA synthesis of an ovarian cancer cell line and inhibits tumor formation in nude mice. The PI has also demonstrated that the transcriptional regulation of Hsal 2 is controlled by two independent promoters and that Hsal 2 promoter usage is altered in some human cancers. In mice, Hsal 2 is able to bind to the large T antigen of polyoma virus, a virus that induces a broad variety of neoplasms. His studies provide strong evidence that Hsal 2 may be a potential tumor suppressor gene for ovarian cancer. These and other observations led to the hypothesis that Hsal 2 isoforms may play a role in the initiation and development of ovarian cancer. To test this, two specific aims will examine the functional roles and underlying mechanisms of expression of Hsal 2 isoforms. Aim 1 will determine the role of altered Hsal 2 isoform expression in ovarian cancer initiation and progression by studying the effect of Hsal 2 isoform overexpression on tumorigenicity, identifying target genes that are subordinate to Hsal 2 isoform expression, and characterizing upstream regulators of Hsal 2 isoforms. Aim 2 will determine the underlying mechanism of altered Hsal 2 isoform expression in ovarian cancer by delineating the usage of Hsal 2 P1 and P2 promoters and measuring the methylation status of CpG islands in Hsal 2 isoform promoters and correlating this with their expression in ovarian cancer. These studies will provide insight into the mechanism(s) of Hsal 2 in controlling growth and differentiation of ovarian normal epithelial cells. If down-regulation of Hsal 2 is shown to activate certain oncogenic pathways or repress tumor suppressor gene pathway(s) in ovarian cancer cells, therapeutic drugs that specifically target these pathways could be designed.