Gene expression analysis of biological systems driving an organotypic model of endometrial carcinogenesis and chemoprevention.
Gene expression analysis of biological systems driving an organotypic model of endometrial carcinogenesis and chemoprevention.
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DOI：
10.4137/grsb.s344
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Dozmorov I
中科院分区：
文献类型：
--
作者：
Benbrook DM;Lightfoot S;Ranger-Moore J;Liu T;Chengedza S;Berry WL;Dozmorov I
建立了子宫内膜癌变和化学预防的器官型模型，其中暴露于致癌物DMBA（7,12-二甲基苯[a]蒽）的正常子宫内膜器官型培养物，在缺乏（但不存在）随后用柔性类异黄酮（Flex-Het）（称为SHetA2）治疗的情况下发展为癌表型。基于细胞核核特征的判别函数和琼脂克隆测定证实了这些组织学变化。使用内部标准方法对微阵列数据进行解释，确定了由c-myc、p53、TNFα和Jun基因控制的与致癌和化学预防相关的主要途径。高变基因功能关联的聚类分析表明，癌变伴随着包括肿瘤坏死因子α (TNFα)、c-myc和表皮生长因子受体（EGF-R）在内的基因模块与包括胰岛素样生长因子i受体（IGF-IR）、p53和Jun基因在内的基因模块之间的刺激关联。参与这些系统的两种分泌蛋白，tenascin C和inhibin A，在蛋白水平上得到了验证。Tenascin C是一种EGF-R配体，因此可能有助于增加EGF-R参与癌变。已知的分子系统在DMBA和子宫内膜癌发生和化学预防中的作用支持了该模型的有效性以及SHetA2在化学预防中的潜在临床应用。
An organotypic model of endometrial carcinogenesis and chemoprevention was developed in which normal endometrial organotypic cultures exposed to the carcinogen, DMBA (7,12-dimethylbenz[a]anthracene), developed a cancerous phenotype in the absence, but not presence of subsequent treatment with a flexible heteroarotinoid (Flex-Het), called SHetA2. A discriminant function based on karyometric features of cellular nuclei and an agar clonogenic assay confirmed these histologic changes. Interpretation of microarray data using an internal standard approach identified major pathways associated with carcinogenesis and chemoprevention governed by c-myc, p53, TNFα and Jun genes. Cluster analysis of functional associations of hypervariable genes demonstrated that carcinogenesis is accompanied by a stimulating association between a module of genes that includes tumor necrosis factor α (TNFα), c-myc, and epidermal growth factor-receptor (EGF-R) and a module that includes insulin-like growth factor I-receptor (IGF-IR), p53, and Jun genes. Two secreted proteins involved in these systems, tenascin C and inhibin A, were validated at the protein level. Tenascin C is an EGF-R ligand, and therefore may contribute to the increased EGF-R involvement in carcinogenesis. The known roles of the identified molecular systems in DMBA and endometrial carcinogenesis and chemoprevention supports the validity of this model and the potential clinical utility of SHetA2 in chemoprevention.