Profiling follicle stimulating hormone-induced gene expression changes in normal and malignant human ovarian surface epithelial cells
Profiling follicle stimulating hormone-induced gene expression changes in normal and malignant human ovarian surface epithelial cells
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DOI：
10.1038/sj.onc.1206437
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发表时间：
2003-07-03
期刊：
影响因子：
8
通讯作者：
Syed, V
中科院分区：
文献类型：
--
作者：
Ho, SM;Lau, KM;Syed, V
流行病学数据表明，垂体促性腺激素（FSH）既是上皮性卵巢癌的危险因素，也是上皮性卵巢癌的保护剂。然而，人们对这种激素如何在卵巢癌发生中发挥如此相反的作用知之甚少。含有 2400 个命名基因的互补 DNA 微阵列用于检查卵巢癌 (OC) 和永生化正常人卵巢表面上皮 (HOSE) 细胞系中 FSH 诱导的基因表达变化。阵列数据的双向 t 统计分析在 HOSE 和从患者建立的已建立的 OC 细胞系（OVCA 细胞尖）中鉴定出两组不同的 FSH 调节基因。在 HOSE 细胞系中，FSH 增加了 312 个基因中 57% 的表达，下调了 43%。相比之下，FSH 降低了 OVCA 细胞系中 177 个基因中 92% 的表达。 HOSE 细胞系中除 18 个受 FSH 影响的基因外，所有其他基因均与 OVCA 细胞系中改变的基因不同。在 18 个重叠基因中，有 9 个基因在 FSH 攻击后表现出相同的变化方向，而其他 9 个基因在 HOSE 和 OVCA 细胞尖齿之间的反应表现出不一致。实时 RT-PCR 证实了 FSH 诱导的九个基因中的七个基因的差异表达。基因特异性反义寡核苷酸 (ODN) 用于抑制 HOSE 和 OVCA 细胞中编码 GTP 酶激活蛋白 (rap1GAP)、neogenin 和 Restin 的基因表达。 neogenin 和 Restin 的反义 ODN（而非 rap1GAP 的反义 ODN）可有效抑制 OVCA 细胞生长、减少增殖细胞核抗原表达并增加 caspase 3 活性。此外，rap1GAP 的 ODN 被进一步证明在改变 OVCA 细胞系的迁移特性方面无效。 HOSE细胞增殖不受任何反义ODN处理的影响。总之，基因分析数据首次揭示，FSH 通过一组假定的癌基因/肿瘤抑制因子的差异调节，可能对 OVCA 细胞与 HOSE 细胞发挥不同的生物学作用。具体而言，发现新生蛋白和 Restin 对 OC 细胞表现出增殖/存活作用。
Epidemiological data have implicated the pituitary gonadotropin follicle stimulating hormone (FSH) as both a risk factor for and a protective agent against epithelial ovarian cancer. Yet, little is known about how this hormone could play such opposing roles in ovarian carcinogenesis. Complementary DNA microarrays containing 2400 named genes were used to examine FSH-induced gene expression changes in ovarian cancer (OC) and immortalized normal human ovarian surface epithelial (HOSE) cell lines. Two-way t-statistics analyses of array data identified two distinct sets of FSH-regulated genes in HOSE and in established OC cell lines established from patients (OVCA cell tines). Among the HOSE cell lines, FSH increased expression of 57% of the 312 genes and downregulated 43%. In contrast, FSH diminished expression of 92% of the 177 genes in the OVCA cell lines. All but 18 of the genes affected by FSH in HOSE cell lines were different from those altered in OVCA cell lines. Among the 18 overlapping genes, nine genes exhibited the same direction of change following FSH challenge, while the other nine showed discordance in response between HOSE and OVCA cell tines. The FSH-induced differential expression of seven out of nine genes was confirmed by real-time RT-PCR. Gene-specific antisense otigonuleotides (ODNs) were used to inhibit the expression of genes encoding GTPase activating protein (rap1GAP), neogenin, and restin in HOSE and OVCA cells. Antisense ODNs to neogenin and restin, but not an antisense ODN to rap1GAP, were effective in inhibiting OVCA cell growth, diminishing proliferating cell nuclear antigen expression, and increasing caspase 3 activities. Furthermore, the ODN to rap1GAP was further shown to be ineffective in altering migration properties of OVCA cell lines. HOSE cell proliferation was not affected by treatment with any of the antisense ODNs. In summary, gene profiling data reveal for the first time that FSH may exert different biological actions on OVCA cells than on HOSE cells, by differential regulation of a set of putative oncogenes/tumor suppressors. Specifically, neogenin and restin were found to exhibit proproliferation/survival action on OC cells.