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生-科学家，这与他之前的经验有很大的不同。 实现这一目标的关键是开展所概述的实践和教学培训以及其他辅导活动。 总体研究目标是阐明同源异型盒基因Hsal 2在卵巢癌发生和发展中的作用。 确定这种非常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，与果蝇中的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。 该基因的再表达抑制卵巢癌细胞系的生长和DNA合成，并抑制裸鼠中的肿瘤形成。 PI还证明了HsaI 2的转录调节由两个独立的启动子控制，并且HsaI 2启动子的使用在一些人类癌症中改变。 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。 他的研究为Hsal 2可能是卵巢癌的潜在抑癌基因提供了强有力的证据。 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起作用的假设。 为了测试这一点，两个具体的目标将检查的功能作用和潜在的机制表达的Hsal 2亚型。 目的1通过研究Hsal 2亚型过表达对致瘤性的影响，鉴定Hsal 2亚型表达的靶基因，并表征Hsal 2亚型的上游调控因子，确定Hsal 2亚型表达改变在卵巢癌发生和发展中的作用。 目的2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Hsal 2亚型的表达相关联，来确定卵巢癌中Hsal 2亚型表达改变的潜在机制。 这些研究将为深入了解Hsal 2在控制卵巢正常上皮细胞生长和分化中的作用机制提供线索。 如果Hsal 2的下调显示出在卵巢癌细胞中激活某些致癌途径或抑制肿瘤抑制基因途径，则可以设计特异性靶向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.