Analysis of protein kinase C delta (PKCδ) expression in endometrial tumors
Analysis of protein kinase C delta (PKCδ) expression in endometrial tumors
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DOI：
10.1016/j.humpath.2007.05.023
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发表时间：
2008-01-01
期刊：
影响因子：
3.3
通讯作者：
Bradford, Andrew P.
中科院分区：
文献类型：
--
作者：
Reno, Elaine M.;Haughian, James M.;Bradford, Andrew P.
子宫内膜癌是美国最常见的妇科恶性肿瘤。然而，其潜在的分子机制尚不清楚；几乎没有预后指标被确定。蛋白激酶C(PKC)家族已被证明调节恶性转化的关键途径；在子宫内膜肿瘤中，PKC表达和活性的变化与更具侵袭性的表型和不良预后有关。我们最近发现，PKC Delta是子宫内膜癌细胞凋亡和细胞存活的关键调节因子；然而，在子宫内膜肿瘤中，PKC Delta的水平尚未确定。我们用免疫组织化学方法检测了正常子宫内膜和增生性子宫内膜样癌中PKC Delta蛋白的表达。正常子宫内膜腺上皮内有丰富的PKC三角胞核和胞浆染色。在子宫内膜肿瘤中，随着肿瘤分级的增加，PKC Delta的表达强度和染色比例均降低，并且PKC Delta优先从细胞核中消失。与这些观察结果一致的是，来自低分化肿瘤的子宫内膜癌细胞株与高分化肿瘤株相比，其PKC增量水平降低。依托泊苷作用于子宫内膜癌细胞后，PKC增量由胞浆移位至胞核，并诱导细胞凋亡。PKC Delta的表达减少，特别是在细胞核中，可能会损害细胞的凋亡能力，可能会导致对化疗的耐药性。我们的结果表明，PKC Delta的缺失是子宫内膜恶性程度和肿瘤分级增加的一个指标。因此，PKC Delta在子宫内膜癌中可能是一种肿瘤抑制因子。(C)2008 Elsevier Inc.保留所有权利。
Endometrial cancer is the most common gynecologic malignancy in the United States. However, its underlying molecular mechanisms are poorly understood; and few prognostic indicators have been identified. The protein kinase C (PKC) family has been shown to regulate pathways critical to malignant transformation; and in endometrial tumors, changes in PKC expression and activity have been linked to a more aggressive phenotype and poor prognosis. We have recently shown that PKC delta is a critical regulator of apoptosis and cell survival in endometrial cancer cells; however, PKC delta levels in endometrial tumors had not been determined. We used immunohistochemistry to examine PKC delta protein levels in normal endometrium and endometrioid carcinomas of increasing grade. Normal endometrium exhibited abundant nuclear and cytoplasmic staining of PKC delta confined to glandular epithelium. In endometrial tumors, decreased PKC delta expression, both in intensity and fraction of epithelial cells stained, was observed with increasing tumor grade, with PKC delta being preferentially lost from the nucleus. Consistent with these observations, endometrial cancer cell lines derived from poorly differentiated tumors exhibited reduced PKC delta levels relative to well-differentiated lines. Treatment of endometrial cancer cells with etoposide resulted in a translocation of PKC delta from cytoplasm to nucleus concomitant with induction of apoptosis. Decreased PKC delta expression, particularly in the nucleus, may compromise the ability of cells to undergo apoptosis, perhaps conferring resistance to chemotherapy. Our results indicate that loss of PKC delta is an indicator of endometrial malignancy and increasing grade of cancer. Thus, PKC delta may function as a tumor suppressor in endometrial cancer. (c) 2008 Elsevier Inc. All rights reserved.