Genetic determinants of FOXM1 overexpression in epithelial ovarian cancer and functional contribution to cell cycle progression.
Genetic determinants of FOXM1 overexpression in epithelial ovarian cancer and functional contribution to cell cycle progression.
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FOXM1上皮卵巢癌中FOXM1过表达的遗传决定因素以及对细胞周期进程的功能贡献。
DOI：
10.18632/oncotarget.4546
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发表时间：
2015-09-29
期刊：
影响因子：
--
通讯作者：
Karpf AR
中科院分区：
文献类型：
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作者：
Barger CJ;Zhang W;Hillman J;Stablewski AB;Higgins MJ;Vanderhyden BC;Odunsi K;Karpf AR
FOXM1 转录因子网络在高级别浆液性卵巢癌 (HGSOC) 中经常被激活，这是上皮性卵巢癌 (EOC) 最常见和致命的亚型。我们使用原代人 EOC 组织、HGSOC 细胞系、小鼠和人卵巢表面上皮 (OSE) 细胞以及小鼠转基因卵巢癌模型来研究 EOC 中 FOXM1 过表达的遗传决定因素，并开始定义其对疾病病理学的功能贡献。癌症基因组图谱 (TCGA) 数据表明，FOXM1 位点在 HGSOC 的约 12% 中扩增，高于所检查的任何其他肿瘤类型，并且 FOXM1 扩增与表达增加和生存率低相关。在一组独立的原发性 EOC 组织中，FOXM1 表达与晚期阶段和级别相关。在三种已知的 FOXM1 亚型中，FOXM1c 在 EOC 中表达量最高。在小鼠 OSE 细胞中，联合敲除 Rb1 和 Trp53 可协同诱导 FOXM1。一致的是，用 SV40 大 T 抗原永生化的人 OSE 细胞 (IOSE-SV) 的 FOXM1 表达显着高于用 hTERT 永生化的 OSE (IOSE-T)。 FOXM1 在 Rb1/Trp53 联合破坏驱动的小鼠卵巢肿瘤中过度表达。 IOSE-SV 细胞中 FOXM1 的诱导部分依赖于 E2F1，并且 FOXM1 表达与人 EOC 组织中 E2F1 表达相关。最后，FOXM1 在人类 OSE 和 HGSOC 细胞模型中对细胞周期进程和相关靶基因表达做出了功能性贡献。总之，基因扩增、p53 和 Rb 破坏以及 E2F1 激活驱动 EOC 中 FOXM1 的表达，而 FOXM1 促进 EOC 细胞模型中的细胞周期进展。
The FOXM1 transcription factor network is frequently activated in high-grade serous ovarian cancer (HGSOC), the most common and lethal subtype of epithelial ovarian cancer (EOC). We used primary human EOC tissues, HGSOC cell lines, mouse and human ovarian surface epithelial (OSE) cells, and a murine transgenic ovarian cancer model to investigate genetic determinants of FOXM1 overexpression in EOC, and to begin to define its functional contribution to disease pathology. The Cancer Genome Atlas (TCGA) data indicated that the FOXM1 locus is amplified in ~12% of HGSOC, greater than any other tumor type examined, and that FOXM1 amplification correlates with increased expression and poor survival. In an independent set of primary EOC tissues, FOXM1 expression correlated with advanced stage and grade. Of the three known FOXM1 isoforms, FOXM1c showed highest expression in EOC. In murine OSE cells, combined knockout of Rb1 and Trp53 synergistically induced FOXM1. Consistently, human OSE cells immortalized with SV40 Large T antigen (IOSE-SV) had significantly higher FOXM1 expression than OSE immortalized with hTERT (IOSE-T). FOXM1 was overexpressed in murine ovarian tumors driven by combined Rb1/Trp53 disruption. FOXM1 induction in IOSE-SV cells was partially dependent on E2F1, and FOXM1 expression correlated with E2F1 expression in human EOC tissues. Finally, FOXM1 functionally contributed to cell cycle progression and relevant target gene expression in human OSE and HGSOC cell models. In summary, gene amplification, p53 and Rb disruption, and E2F1 activation drive FOXM1 expression in EOC, and FOXM1 promotes cell cycle progression in EOC cell models.