The Roles of HBXAP Gene in Ovarian Cancer

描述（由申请人提供）：本研究的目的是描述最近发现的肿瘤相关基因HBXAP（也称为Rsf-1）的特征，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绘卵巢癌的分子遗传学变化，并确定了一个新的扩增基因，HBXAP（Rsf-1），在卵巢癌。HBXAP的扩增和过表达与临床标本中最具侵袭性的卵巢癌类型显著相关。已知HBXAP与hSNF 2 H相互作用形成染色质重塑复合物。事实上，我们证明了HBXAP与hSNF 2 H在卵巢癌细胞中共免疫沉淀，HBXAP的表达促进了p53突变细胞中的肿瘤细胞生长和存活，而不是p53野生型细胞。基于上述发现，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，并且在p53突变细胞中，HBXAP水平的增加通过其与hSNF 2 H的结合促进肿瘤进展。此外，HBXAP可作为临床前小鼠肿瘤模型中的潜在治疗靶点。为了验证上述假设，我们提出了四个紧密结合的目标。目标1：确定HBXAP和hSNF 2 H染色质重塑复合物的形成是否是HBXAP过表达的卵巢癌细胞存活所必需的。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过表达与突变型p53联合是否对肿瘤发生和/或肿瘤进展至关重要。目的4：确定HBXAP靶向治疗小鼠卵巢癌移植瘤的抗肿瘤作用。揭示破译肿瘤促进基因功能的分子背景对于了解癌症发展的发病机制至关重要，并且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，HBXAP（一种染色质重塑基因）的扩增和过表达与最具侵袭性的卵巢癌类型显著相关。本研究的目的是描述HBXAP上调如何促进卵巢癌的发展和进展。揭示破译肿瘤促进基因功能的分子背景对于了解癌症发展的发病机制至关重要，并且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.