Role of Hsal 2 in Ovarian Cancer

描述（由申请人提供）：马博士的总体目标是获得在人类癌症生物学领域进行研究的技能和知识，并成为该领域的独立医师-科学家，这与他之前的经历有很大的不同。实现这一目标的关键是开展概述的实践和教学培训以及其他指导活动。总体研究目标是阐明同源盒基因Hsal 2在卵巢癌发生和发展中的作用。确定这种极具侵袭性的癌症的潜在机制对于开发新疗法和提高生存率至关重要。PI先前的研究证明了一种新的肿瘤抑制基因Hsal 2，与果蝇的Sal同源盒基因同源，在大多数卵巢上皮癌细胞中被改变或缺失。该基因的重新表达抑制卵巢癌细胞系的生长和DNA合成，并抑制裸鼠肿瘤的形成。PI还证明了Hsal 2的转录调控是由两个独立的启动子控制的，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，多瘤病毒是一种能诱发多种肿瘤的病毒。他的研究提供了强有力的证据，证明Hsal - 2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了Hsal 2亚型可能在卵巢癌的发生和发展中发挥作用的假设。为了验证这一点，两个特定的目标将检查Hsal 2亚型的功能作用和潜在的表达机制。目的1将通过研究Hsal 2异构体过表达对致瘤性的影响，鉴定隶属于Hsal 2异构体表达的靶基因，以及表征Hsal 2异构体的上游调节因子，确定改变的Hsal 2异构体表达在卵巢癌发生和进展中的作用。目的2将通过描述Hsal 2 P1和P2启动子的使用，测量Hsal 2亚型启动子中CpG岛的甲基化状态，并将其与卵巢癌中的表达联系起来，确定卵巢癌中Hsal 2亚型表达改变的潜在机制。这些研究将进一步揭示Hsal - 2调控卵巢正常上皮细胞生长和分化的机制。如果发现下调Hsal - 2可激活卵巢癌细胞中的某些致癌途径或抑制肿瘤抑制基因途径，则可以设计出专门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.