Somatic expression of ENRAGE is associated with obesity status among patients with clear cell renal cell carcinoma
Somatic expression of ENRAGE is associated with obesity status among patients with clear cell renal cell carcinoma
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DOI：
10.1093/carcin/bgt485
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发表时间：
2014-04-01
期刊：
影响因子：
4.7
通讯作者：
Parker, Alexander S.
中科院分区：
文献类型：
--
作者：
Eckel-Passow, Jeanette E.;Serie, Daniel J.;Parker, Alexander S.
肥胖和ccRCC的发展之间的关联已经建立;然而，分子机制尚不清楚。我们使用多阶段设计来鉴定和验证ENERGY的过度表达是肥胖相关的体细胞改变，肥胖和肾透明细胞癌（ccRCC）的发展之间的关联已经在文献中建立，但是，关于这种关联背后的分子机制的数据有限。因此，我们使用多阶段设计来鉴定和验证与肥胖相关的ccRCC相关的基因。我们进行了一项微阵列研究，并比较了肥胖和非肥胖受试者在ccRCC肿瘤和患者匹配的正常肾组织中的基因表达。分析按吸烟状态分层，随后对合并队列进行分析。主要目的是鉴定肥胖和非肥胖受试者之间的ccRCC肿瘤表达的倍数变化不同于患者匹配的正常肾组织中的倍数变化的基因。因此，我们利用混合模型，并评估了组织类型与肥胖状态的相互作用项。采用逆转录聚合酶链反应（RTPCR）对一个独立队列进行靶向验证。在微阵列研究中鉴定了ENERGY，随后使用RTPCR验证其具有统计学显著的组织类型与肥胖状态的相互作用。具体而言，尽管ENGINE在正常组织中在肥胖和非肥胖受试者中类似地表达，但它在患者匹配的ccRCC肿瘤组织中上调。此外，ENERGY在von Hippel Lindau基因的野生型肿瘤和总体生存期较差的受试者的肿瘤中上调。总之，我们提供的证据表明，在ccRCC肿瘤组织中ENGINEER的过表达是一种肥胖相关的体细胞改变。ENERGY的上调可导致ENERGY受体的局部自分泌刺激，从而支持癌症进展。
An association between obesity and development of ccRCC has been established; however, the molecular mechanisms are unknown. We used a multistage design to identify and validate that overexpression of ENRAGE is an obesity-associated somatic alteration.An association between obesity and development of clear cell renal cell carcinoma (ccRCC) has been established in the literature; however, there are limited data regarding the molecular mechanisms that underlie this association. Therefore, we used a multistage design to identify and validate genes that are associated with obesity-related ccRCC. We conducted a microarray study and compared gene expression between obese and non-obese subjects in ccRCC tumors and patient-matched normal kidney tissues. Analyses were stratified by smoking status and subsequently performed on the combined cohort. The primary objective was to identify genes where the fold change of ccRCC tumor expression between obese and non-obese subjects was different than the fold change in the patient-matched normal kidney tissue. Thus, we utilized a mixed model and evaluated the tissue type-by-obesity status interaction term. Targeted validation was performed using reverse transcriptionpolymerase chain reaction (RTPCR) on an independent cohort. ENRAGE was identified in the microarray study and subsequently validated using RTPCR to have a statistically significant tissue type-by-obesity status interaction. Specifically, although ENRAGE is similarly expressed across obese and non-obese subjects in normal tissue, it is upregulated in the patient-matched ccRCC tumor tissue. Additionally, ENRAGE is upregulated in tumors that are wild-type for the von Hippel Lindau gene and in tumors for subjects with poorer overall survival. In summary, we provide evidence that overexpression of ENRAGE in ccRCC tumor tissue is an obesity-associated somatic alteration. Upregulation of ENRAGE could lead to local, autocrine stimulation of the RAGE receptor and thus support cancer progression.