Granulosa cell tumor with activated mTOR-HIF-1α-VEGF pathway
Granulosa cell tumor with activated mTOR-HIF-1α-VEGF pathway
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DOI：
10.1111/j.1447-0756.2009.01127.x
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发表时间：
2010-04-01
影响因子：
1.6
通讯作者：
Osamura, R. Yoshiyuki
中科院分区：
文献类型：
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作者：
Miyazawa, Masaki;Yasuda, Masanori;Osamura, R. Yoshiyuki
分析了缺氧诱导因子-1 α (HIF-1 α)在多种妇科肿瘤中的dna结合活性。在所研究的肿瘤中，发现了高水平的dna结合HIF-1 α活性，尽管仅限于一例成人型颗粒细胞肿瘤（GCT）。在这个病例中，一名60岁的女性HIF-1 α的免疫组织化学表达明显。哺乳动物雷帕霉素靶蛋白（mTOR）和磷酸化mTOR （p-mTOR）的表达也被标记，血管内皮生长因子（VEGF）适度表达。为了比较表达谱，我们连续使用了11例成人型GCT。所有病例均有HIF-1 α和mTOR的显著表达，但12例中有4例p-mTOR有中度至显著表达。VEGF在所有病例中均有不同程度的表达。基于雷帕霉素（依维莫司）治疗导致mTOR通路下调会抑制肿瘤细胞生长的证据，我们设计了一项使用GCT细胞系的实验研究，以阐明HIF-1 α和VEGF表达是否下降。结果，p-mTOR、HIF-1 α和VEGF的表达受到抑制，而mTOR的表达没有受到抑制。结论是，mtor靶向治疗可能是一种有希望的策略，用于某些具有活化mTOR-HIF-1 α - vegf通路的GCT。
The DNA-binding activity of hypoxia-inducible factor-1 alpha (HIF-1 alpha) has been analyzed for various gynecological tumors. Among the tumors that were studied, there was a finding of a high level of DNA-binding HIF-1 alpha activity, although it was limited to one case of adult type granulosa cell tumor (GCT). In this case a 60-year-old female had marked immunohistochemical expression of HIF-1 alpha. The expressions of the mammalian target of rapamycin (mTOR) and phosphorylated-mTOR (p-mTOR) were also marked, and vascular endothelial growth factor (VEGF) was moderately expressed. To compare the expression profiles, 11 consecutive cases with adult type GCT were used. All cases showed marked expressions of HIF-1 alpha and mTOR, but p-mTOR expression was moderately to markedly observed in four of the 12 cases. VEGF was expressed in all cases in varying degrees. Based on the evidence that downregulation of the mTOR pathway due to treatment with rapamycin (everolimus) would suppress tumor cell growth, an experimental study using the GCT cell line was designed to clarify whether HIF-1 alpha and VEGF expressions decline. As a result, the expressions of p-mTOR, HIF-1 alpha and VEGF were suppressed, but those of mTOR were not. It was concluded that mTOR-targeted therapy may represent a promising strategy for some GCT with an activated mTOR-HIF-1 alpha-VEGF pathway.