Atypical PKCι contributes to poor prognosis through loss of apical-basal polarity and Cyclin E overexpression in ovarian cancer
Atypical PKCι contributes to poor prognosis through loss of apical-basal polarity and Cyclin E overexpression in ovarian cancer
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DOI：
10.1073/pnas.0505641102
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发表时间：
2005-08-30
影响因子：
11.1
通讯作者：
Mills, GB
中科院分区：
文献类型：
--
作者：
Eder, AM;Sui, XM;Mills, GB
我们表明，非典型的PKC IOTA在上皮细胞极性的建立和维持中起着至关重要的作用，在基因组上放大和过表达浆液性上皮卵巢癌。此外，在所有浆液性卵巢癌中，PKC IOTA蛋白明显增加或误置。 PKC IOTA DNA拷贝数增加与浆液上皮卵巢癌中无进展生存的降低有关。在果蝇中的体内上皮组织模型中，持续活跃的非典型PKC的过表达会导致顶质基质极性的缺陷，增加的细胞周期蛋白E蛋白表达并增加增殖。与果蝇模型相似，PKC IOTA蛋白水平增加与卵巢癌中的细胞周期蛋白表达和增殖有关。在非全卵巢癌中，PKC IOTA蛋白水平升高，特别是在存在细胞周期蛋白E的情况下，与总体生存率明显降低有关。这些结果暗示PKC IOTA是调节上皮细胞极性和增殖的卵巢癌中潜在的致癌基因，并表明PKC IOTA是治疗的新靶标。
We show that atypical PKC iota, which plays a critical role in the establishment and maintenance of epithelial cell polarity, is genomically amplified and overexpressed in serous epithelial ovarian cancers. Furthermore, PKC iota protein is markedly increased or mislocalized in all serous ovarian cancers. An increased PKC iota DNA copy number is associated with decreased progression-free survival in serous epithelial ovarian cancers. In a Drosophila in vivo epithelial tissue model, overexpression of persistently active atypical PKC results in defects in apical-basal polarity, increased Cyclin E protein expression, and increased proliferation. Similar to the Drosophila model, increased PKC iota proteins levels are associated with increased Cyclin E protein expression and proliferation in ovarian cancers. In nonserous ovarian cancers, increased PKC iota protein levels, particularly in the presence of Cyclin E, are associated with markedly decreased overall survival. These results implicate PKC iota as a potential oncogene in ovarian cancer regulating epithelial cell polarity and proliferation and suggest that PKC iota is a novel target for therapy.