The Roles of HBXAP Gene in Ovarian Cancer

描述(由申请人提供)：这项研究的目标是表征最近发现的肿瘤相关基因HBXAP(也称为RSF-1)，它在卵巢癌中被扩增。在过去的几年里，我们应用全基因组分析来描绘卵巢癌的分子遗传学变化，并在卵巢癌中发现了一个新的扩增基因HBXAP(RSF-1)。在临床标本中，HBXAP的扩增和过度表达与最具侵袭性的卵巢癌显著相关。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与hSNF2H在卵巢癌细胞中共沉淀，HBXAP的表达促进了p53突变细胞的生长和存活，但对p53野生型细胞没有促进作用。根据以上发现，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水平的增加通过与hSNF2H结合而促进肿瘤的进展。此外，HBXAP可能在临床前小鼠肿瘤模型中作为潜在的治疗靶点。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是HBXAP过表达的卵巢癌细胞生存所必需的。目的：探讨p53基因突变在HBXAP促肿瘤作用中的作用。目的3：评估HBXAP的过度表达与突变型P53蛋白的联合作用是否对肿瘤的发生和/或进展起重要作用。目的：通过靶向HBXAP对小鼠卵巢癌移植瘤的抗肿瘤作用。揭示促进肿瘤基因功能的分子背景对于理解癌症发展的发病机制是必不可少的，并可能对新的癌症治疗具有翻译意义。 公共卫生相关性：先前的研究表明，染色质重塑基因HBXAP的扩增和过度表达与最具侵袭性的卵巢癌密切相关。本研究的目的是描述HBXAP上调如何在卵巢癌的发生和发展中起作用。揭示促进肿瘤基因功能的分子背景对于理解癌症发展的发病机制是必不可少的，并可能对新的癌症治疗具有翻译意义。

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.