Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma
Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma
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DOI：
10.1038/cr.2008.70
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发表时间：
2008-07-01
期刊：
影响因子：
44.1
通讯作者：
Feng, Youji
中科院分区：
文献类型：
--
作者：
Huang, Yan;Hua, Keqin;Feng, Youji
有证据表明，促卵泡激素（FSH）可以通过增加癌细胞中血管内皮生长因子（VEGF）的表达来促进卵巢癌的新生血管形成，尽管这一过程的潜在分子机制尚不清楚。因此，我们研究了FSH对卵巢癌细胞系SKOV-3和ES-2中VEGF表达的影响。FSH治疗显著增加VEGF表达，且呈剂量和时间依赖性。此外，FSH处理可提高survivin和缺氧诱导因子-1 （HIF-1 α）的表达。敲低survivin或HIF-1 α抑制VEGF表达，但只有敲低survivin抑制fsh刺激的VEGF表达。用磷酸肌苷3-激酶(PI3K)/AKT抑制剂LY294002预处理可以中和FSH诱导的survivin表达增强，但用丝裂原活化蛋白激酶/细胞外信号调节激酶抑制剂U0126处理则没有这种效果。我们进一步发现卵巢浆液性囊腺癌样本中AKT和磷酸化AKT （pAKT）蛋白染色阳性的发生率明显高于良性卵巢囊腺瘤样本（p < 0.01）。AKT和pAKT表达的卵巢浆液性囊腺癌患者的5年生存率仅为15%左右，而AKT和pAKT不表达的卵巢浆液性囊腺癌患者的5年生存率约为80%。综上所述，这些结果表明FSH通过上调PI3K/AKT信号通路激活的survivin表达来增加VEGF的表达。了解PI3K/AKT通路在fsh刺激的survivin和VEGF表达中的作用，将有助于评估卵巢浆液性囊腺癌患者的预后，并寻求有效的治疗方法。
There is evidence to suggest that follicle-stimulating hormone (FSH) can facilitate the neovascullarization of ovarian cancers by increasing vascular endothelial growth factor (VEGF) expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose- and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxia-inducible factor-1 (HIF-1 alpha). Knockdown of survivin or HIF-1 alpha suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase (PI3K)/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT (pAKT) protein staining than did benign ovarian cystadenoma samples (p < 0.01). The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursuing effective treatment against this disease.