Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer
Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer
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DOI：
10.1002/cncr.22195
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发表时间：
2006-10-15
期刊：
影响因子：
6.2
通讯作者：
Ramon y Cajal, Santiago
中科院分区：
文献类型：
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作者：
Castellvi, Josep;Garcia, Angel;Ramon y Cajal, Santiago
背景资料。生长因子受体和细胞信号因子在人类癌症中起着至关重要的作用，并在卵巢肿瘤中进行了研究，结果各不相同。细胞信号涉及多条途径和无数可以突变或扩增的因子。细胞信号转导通过哺乳动物靶标雷帕霉素(MTOR)和细胞外调节蛋白(ERK)途径以及一些下游分子，如4E结合蛋白1(4EBP1)、真核细胞启动因子4E和p70核糖体蛋白S6激酶(P70S6K)。本研究的目的是分析这些通路在卵巢癌中的真实作用，将它们与临床病理特征相关联，并确定传递个体增殖信号并与病理分级和预后相关的因素，而不考虑上游特定的致癌改变。方法：129例卵巢上皮性肿瘤，包括20例浆液性囊腺瘤、7例粘液性囊腺瘤、I型浆液性交界性肿瘤、16例粘液性交界性肿瘤、29例浆液性癌、16例子宫内膜样癌、15例透明细胞癌和15例粘液性癌。结果129例卵巢肿瘤中，c-erb-B2阳性率为17.8%，EGFR阳性率为9.3%，p-AKT阳性率为47.3%，p-ERK阳性率为58.9%，p-4EBP1、p70S6K、S6和ERK阳性率分别为41.1%和26.4%，p-AKT阳性率为58.9%，p-4EBP1阳性率为41.1%。P-S6阳性率为15.5%。尽管EGFR、p-AKT和p-ERK在良性肿瘤、交界性肿瘤和恶性肿瘤中的表达没有差异，但c-erb-B2、p-4EBP1、p-p70S6K和p-S6在恶性肿瘤中的表达明显更高。在多因素分析中，只有p-4EBP1的表达有预后意义(P=.005)，只有手术分期和p-4EBP1的表达有统计学意义。结论：在卵巢癌患者中，p-4EBP1的显著表达与肿瘤的高级别和预后不良有关，而与上游其他致癌改变无关。这一发现支持将该因子作为卵巢癌细胞信号传递的标志或关键因子的研究，该因子可能在增殖细胞信号的传递中起关键作用，并可能反映该途径在卵巢肿瘤中的真正致癌作用。(C)2006年美国癌症协会。
BACKGROUND. Growth factor receptors and cell signaling factors play a crucial role in human carcinomas and have been studied in ovarian tumors with varying results. Cell signaling involves multiple pathways and a myriad of factors that can be mutated or amplified. Cell signaling is driven through the mammalian target of rapamycin (mTOR) and extracellular regulated kinase (ERK) pathways and by some downstream molecules, such as 4E binding protein 1 (4EBP1), eukaryotic initiation factor 4E, and p70 ribosomal protein S6 kinase (p70S6K). The objectives of this study were to analyze the real role that these pathways play in ovarian cancer, to correlate them with clinicopathologic characteristics, and to identify the factors that transmit individual proliferation signals and are associated with pathologic grade and prognosis, regardless specific oncogenic alterations upstream.METHODS. One hundred twenty-nine ovarian epithelial tumors were studied, including 20 serous cystadenomas, 7 mucinous cystadenomas, I I serous borderline tumors, 16 mucinous borderline tumors, 29 serous carcinomas, 16 endometrioid carcinomas, 15 clear cell carcinomas, and 15 mucinous carcinomas. Tissue microarrays were constructed, and immunohistochemistry for the receptors epidermal growth factor receptor (EGFR) and c-erb-B2 was performed and with phosphorylated antibodies for protein kinase B (AKT), 4EBP1, p70S6K, S6, and ERK.RESULTS. Among 129 ovarian neoplasms, 17.8% were positive for c-erb-B2, 9.3% were positive for EGFR, 47.3% were positive for phosphorylated AKT (p-AKT), 58.9% were positive for p-ERK, 41.1% were positive for p-4EBP1, 26.4% were positive for p70S6K, and 15.5% were positive for p-S6. Although EGFR, p-AKT, and p-ERK expression did not differ between benign, borderline, or malignant tumors, c-erb-B2, p-4EBP1, p-p70S6K, and p-S6 were expressed significantly more often in malignant tumors. Only p-4EBP1 expression demonstrated prognostic significance (P =.005), and only surgical stage and p-4EBP1 expression had statistical significance in the multivariate analysis.CONCLUSIONS. in patients with ovarian carcinoma, significant expression of p-4EBP1 was associated with high-grade tumors and a poor prognosis, regardless other oncogenic alterations upstream. This finding supports the study of this factor as a hallmark or pivotal factor in cell signaling in ovarian carcinoma that may crucial in the transmission of the proliferation cell signal and may reflect the real oncogenic role of this pathway in ovarian tumors. (c) 2006 American Cancer Society.