Cyclin E1 deregulation occurs early in secretory cell transformation to promote formation of fallopian tube-derived high-grade serous ovarian cancers.
Cyclin E1 deregulation occurs early in secretory cell transformation to promote formation of fallopian tube-derived high-grade serous ovarian cancers.
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DOI：
10.1158/0008-5472.can-13-2247
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发表时间：
2014-02-15
期刊：
影响因子：
11.2
通讯作者：
Drapkin R
中科院分区：
文献类型：
--
作者：
Karst AM;Jones PM;Vena N;Ligon AH;Liu JF;Hirsch MS;Etemadmoghadam D;Bowtell DD;Drapkin R
现在普遍认为输卵管是高级别浆液性卵巢癌的主要起源部位。然而，人们对输卵管源性浆液性癌的分子发病机制知之甚少，并且很少有实验研究检查人类输卵管细胞的转化。最近的基因组分析发现细胞周期蛋白 E1 (CCNE1) 基因扩增是浆液性卵巢癌的候选致癌驱动因素，因此我们评估了 CCNE1 在浆液性癌发生中的功能作用。 CCNE1 在早期和晚期人类肿瘤样本中表达。在原代人输卵管分泌上皮细胞中，如果 p53 受到损害，CCNE1 表达会赋予未转化细胞恶性特征，从而促进 DNA 损伤的积累，并改变与 DNA 复制应激相关的 DNA 损伤反应基因的转录。我们的研究结果共同证实了这样的假设：Cyclin E1 失调会驱动输卵管分泌细胞的恶性转化，而输卵管分泌细胞是浆液性卵巢癌的起源部位。
Fallopian tube is now generally considered the dominant site of origin for high-grade serous ovarian carcinoma. However, the molecular pathogenesis of fallopian tube-derived serous carcinomas are poorly understood and there are few experimental studies examining the transformation of human fallopian tube cells. Prompted by recent genomic analyses that identified Cyclin E1 (CCNE1) gene amplification as a candidate oncogenic driver in serous ovarian carcinoma, we evaluated the functional role of CCNE1 in serous carcinogenesis. CCNE1 was expressed in early and late stage human tumor samples. In primary human fallopian tube secretory epithelial cells, CCNE1 expression imparted malignant characteristics to untransformed cells if p53 was compromised, promoting an accumulation of DNA damage and altered transcription of DNA damage response genes related to DNA replication stress. Together our findings corroborate the hypothesis that Cyclin E1 dysregulation acts to drive malignant transformation in fallopian tube secretory cells that are the site of origin of serous ovarian carcinomas.