FOXM1及其下游分子网络对浆液性卵巢癌的调控机制与分子分型研究

Serous ovarian carcinoma（SOC ）is the most common subtype of ovarian malignancies with the worst prognosis. The Cancer Genome Atlas (TCGA) project showed that FOXM1 transcription factor network altered in 87% of high grade serous ovarian carcinoma cases，just lower than P53 expression. However, the biological function and molecular mechanism of FOXM1 and its downstream network need further study. We will first determine the functional effect of FOXM1 on tumorigenesis and metastasis of SOC in vitro and in vivo. Then, ChIP-Seq, luciferase assay and bioinformatics analysis will be used to identify the downstream targets that are physically associated with FOXM1. And finally, we will examine the expressions of FOXM1 and its downstream network in SOC patient samples to determine whether their expressions are correlated with tumorigenesis , molecular typing and clinical prognosis. The ultimate goal of this study is to clarify and characterize the functional role and molecular mechanism of FOXM1 and its downstream network in tumorigenesis and metastasis of SOC and provide new molecular targets for molecular typing and individualized treatment.

浆液性卵巢癌（serous ovarian carcinoma，SOC）是卵巢恶性肿瘤中最常见而预后最差的亚型。癌症基因组图谱计划（TCGA）对SOC全基因组分析发现FOXM1信号通路在高级别SOC中异常表达的比率高达87%，仅次于P53，但FOXM1在SOC中的分子调控机制尚未阐明。本课题拟通过干预表达，利用体外和体内实验明确其在SOC中的生物学功能；利用ChIP-Seq、luciferase及生物信息学等方法筛选和鉴定FOXM1下游关键分子；并进一步通过组织芯片分析FOXM1及下游分子的表达状况，以明确其与肿瘤发生发展和分子分型及临床预后的相关性。本研究将有助于揭示FOXM1及下游分子网络调控SOC的分子机制，为本病的分子分型和个体化治疗提供新的分子靶标。

高级别浆液性卵巢癌（high-grade serous ovarian carcinoma，HGSOC）是卵巢恶性肿瘤中最常见而预后最差的亚型。癌症基因组图谱计划（TCGA）对HGSOC全基因组分析发现FOXM1信号通路在HGSOC中异常表达的比率高达87%，但FOXM1在HGSOC中的分子调控机制尚未阐明。基于课题组构建的HGSOC组织芯片的免疫组化染色确认FOXM1在HGSOC中普遍性高表达，并与患者不良预后相关。生物学功能实验证明FOXM1过表达促进卵巢癌细胞增殖和侵袭。RNA-seq结合ChIP-seq联合分析确定了HGSOC中FOXM1转录调控的下游靶基因CCNF与KIF20A。双荧光素酶报告基因和ChIP-qPCR实验确认FOXM1结合到CCNF及KIF20A启动子上转录激活靶基因的表达。基于TCGA和HGSOC组织样本发现CCNF、KIF20A的mRNA和蛋白在HGSOC中表达明显高于正常卵巢或输卵管伞组织。基于HGSOC组织芯片染色同样发现CCNF与KIF20A高表达均与HGSOC患者的不良预后相关。CCNF或KIF20A过表达促进卵巢癌细胞的增殖和侵袭，在FOXM1过表达细胞中分别干扰CCNF或KIF20A表达均能明显减弱FOXM1的促癌功能。此外，课题组发现FOXM1在HGSOC中的高表达除与11%样本中存在FOXM1基因组拷贝数扩增外，HGSOC中TP53基因普遍失活与FOXM1广泛高表达密切相关，这种相关性与TP53突变类型无关。