The Roles of HBXAP Gene in Ovarian Cancer

描述（由申请人提供）：本研究的目的是表征最近发现的肿瘤相关基因HBXAP（也称为rf -1），该基因在卵巢癌中扩增。在过去的几年里，我们应用全基因组分析来描述卵巢癌的分子遗传变化，并在卵巢癌中发现了一个新的扩增基因HBXAP （rf -1）。在临床标本中，HBXAP的扩增和过表达与最具侵袭性的卵巢癌类型显著相关。已知HBXAP与hSNF2H相互作用形成染色质重塑复合体。事实上，我们证明了HBXAP在卵巢癌细胞中与hSNF2H共免疫沉淀，HBXAP的表达促进了p53突变细胞的肿瘤细胞生长和存活，而在p53野生型细胞中则没有。基于以上发现，我们推测p53突变有助于细胞逃避癌基因诱导的生长抑制和凋亡，而在p53突变细胞中，HBXAP水平升高通过与hSNF2H结合促进肿瘤进展。此外，HBXAP可能作为临床前小鼠肿瘤模型的潜在治疗靶点。为了验证上述假设，我们提出了四个紧密结合的目标。目的1：确定HBXAP和hSNF2H染色质重塑复合体的形成是否需要在HBXAP过表达的卵巢癌细胞中存活。目的2：评估p53突变在hbxap诱导的肿瘤促进中的作用。目的3：评估HBXAP与突变型p53的过表达是否对肿瘤发生和/或肿瘤进展至关重要。目的4：检测HBXAP在小鼠卵巢癌异种移植中的抗肿瘤作用。揭示肿瘤促进基因功能的分子背景对了解癌症发展的发病机制至关重要，并可能对新的癌症治疗具有转化意义。

DESCRIPTION (provided by applicant): The objective of this study is to characterize a recently identified tumor-associated gene, HBXAP (also known as Rsf-1), that is amplified in ovarian cancer. Over the past years, we have applied genome-wide analyses to delineate molecular genetic changes in ovarian cancer, and have identified a new amplified gene, HBXAP (Rsf-1), in ovarian carcinomas. Amplification and overexpression of HBXAP are significantly associated with the most aggressive type of ovarian cancer in clinical specimens. It has been known that HBXAP interacts with hSNF2H to form a chromatin remodeling complex. Indeed, we demonstrated that HBXAP co-immunoprecipitated with hSNF2H in ovarian caner cells, and expression of HBXAP promoted tumor cell growth and survival in p53 mutated cells but not in p53 wild-type cells. Based on the above findings, we hypothesize that p53 mutation facilitates cells to evade from the oncogene-induced growth suppression and apoptosis, and in the p53 mutant cells, increased HBXAP levels contributes to tumor progression by its binding to hSNF2H. Furthermore, HBXAP may serve as a potential therapeutic target in a preclinical mouse tumor model. To test the above hypotheses, we propose four closely integrated aims. Aim 1: Determine if formation of the HBXAP and hSNF2H chromatin remodeling complex is required for survival in ovarian cancer cells with HBXAP overexpression. Aim 2: Assess the roles of p53 mutations in HBXAP-induced tumor promotion. Aim 3: Assess if overexpression of HBXAP in combination with mutant p53 is essential for tumorigenesis and/or tumor progression. Aim 4: Determine the anti-tumor effects by targeting HBXAP in mouse ovarian cancer xenografts. Revealing the molecular context in deciphering the functions of a tumor-promoting gene is essential to understand the pathogenesis of cancer development and may have translational implications for new cancer therapy. PUBLIC HEALTH RELEVANCE: Previous studies have shown that amplification and overexpression of HBXAP, a chromatin remodeling gene, are significantly associated with the most aggressive type of ovarian cancer. The objective of the current study is to characterize how HBXAP upregulation contributes to the development and progression of ovarian cancer. Revealing the molecular context in deciphering the functions of a tumor-promoting gene is essential to understand the pathogenesis of cancer development and may have translational implications for new cancer therapy.