The Roles of HBXAP Gene in Ovarian Cancer

摘要 这项研究的目的是鉴定最近发现的肿瘤相关基因HBXAP(也称为 如RSF-1)，它在卵巢癌中被放大。在过去的几年里，我们应用了全基因组分析来 描述卵巢癌的分子遗传学变化，并发现一个新的扩增基因HBXAP (RSF-1)，在卵巢癌。HBXAP的扩增和过度表达与 临床标本中最具侵袭性的卵巢癌。已知HBXAP与 HSNF2H形成染色质重塑复合体。事实上，我们证明了HBXAP联合- HSNF2H在卵巢癌细胞中的免疫共沉淀及HBXAP的表达促进肿瘤细胞生长 在突变型细胞中存活，而在野生型细胞中不存活。基于上述发现，我们假设 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水平的增加通过与其结合而促进肿瘤进展 HSNF2H。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。目标1：确定是否形成了 HBXAP和hSNF2H染色质重塑复合体是卵巢癌细胞生存所必需的 HBXAP过度表达。目的：探讨p53基因突变在HBXAP促肿瘤作用中的作用。目标3： 评估HBXAP过表达与突变型P53是否在肿瘤发生和/或肿瘤中起重要作用 进步。目的：通过靶向HBXAP对小鼠卵巢癌移植瘤的抗肿瘤作用。 揭示分子背景对破译促肿瘤基因的功能是至关重要的 了解癌症发展的发病机制，并可能对新的癌症有翻译意义 心理治疗。叙述性 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。当前研究的目标是 是为了描述HBXAP上调如何促进卵巢癌的发生和发展。 揭示分子背景对破译促肿瘤基因的功能是至关重要的 了解癌症发展的发病机制，并可能对新的癌症有翻译意义 心理治疗。

Abstract 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. Narrative 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.