Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma
Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma
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DOI：
10.1093/carcin/bgn255
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发表时间：
2009-01-01
期刊：
影响因子：
4.7
通讯作者：
Toyokuni, Shinya
中科院分区：
文献类型：
--
作者：
Zhong, Yi;Onuki, Janice;Toyokuni, Shinya
越来越多的研究表明氧化应激与癌症之间存在联系。我们建立了一种由次氮基三乙酸铁（Fe-NTA）诱发的大鼠肾细胞癌（RCC）模型。在这里，我们进行了全基因组分析，以研究基因组改变的特点，并确定参与Fe-NTA诱导的RCC发展的推定基因。基于阵列的比较基因组杂交分析显示，在大多数研究的RCC中，染色体丢失跨越8号染色体，在8 q31 -32处具有常见的缺失，这通过杂合性丢失（洛）分析证实。RCC中或Fe-NTA治疗后的基因表达研究显示，来自8号染色体的34个基因在肾脏中表达的转录水平总体降低。其中，氨基酰化酶1（Acy 1）基因，定位于8 q32，在肾脏中高度表达，在RCC中的表达水平显着降低。在未处理大鼠的肾近端小管细胞的细胞质和细胞核中检测到大量的Acy 1蛋白。Acy 1转染肾癌细胞系抑制增殖和软琼脂集落形成。Acy 1转染后观察到凋亡细胞数量增加。大鼠8 q31 -32染色体区域对应于人类3p21.31-24.1，这是在各种人类癌症中经常发现的洛缺失的热点。因此，Fe-NTA诱导的肾肿瘤模型是研究该区域内的缺失与肿瘤形成之间联系的理想模型。我们的数据表明，Acy 1功能作为一种肿瘤抑制剂，在这个大鼠肾细胞癌模型。
A growing number of studies indicate a link between oxidative stress and cancer. We previously developed a rat model of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Here, we performed a genome-wide analysis to study characteristics of genomic alteration and identify putative genes involved in the development of Fe-NTA-induced RCCs. Array-based comparative genomic hybridization analyses revealed a chromosomal loss spanning chromosome 8 in most of the RCCs studied, with a common deletion at 8q31-32, which was confirmed by loss of heterozygosity (LOH) analysis. Studies of gene expression in RCCs or following Fe-NTA treatment revealed globally decreased transcription levels of 34 genes derived from chromosome 8 that are expressed in the kidney. Among them, the aminoacylase 1 (Acy1) gene, which maps to 8q32 and is highly expressed in the kidney, displayed a significantly decreased level of expression in RCCs. Significant amounts of the Acy1 protein were detected in the cytoplasm as well as in the nuclei of renal proximal tubular cells of untreated rats. Transfection of Acy1 into RCC cell lines inhibited proliferation and colony formation on soft agar. An increased number of apoptotic cells were observed following Acy1 transfection. The rat 8q31-32 chromosomal region corresponds to human 3p21.31-24.1, a hot spot where LOH is frequently found in various human cancers. Thus, Fe-NTA-induced renal tumor model is ideal for studying the link between deletions within this region and tumor formation. Our data demonstrate that Acy1 functions as a tumor suppressor in this rat RCC model.