Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma
Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma
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DOI：
10.1038/labinvest.2009.140
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发表时间：
2010-03-01
影响因子：
5
通讯作者：
Toyokuni, Shinya
中科院分区：
文献类型：
--
作者：
Hu, Qian;Akatsuka, Shinya;Toyokuni, Shinya
在人类中，间皮瘤与石棉暴露有关，特别是青石棉和铁石棉，其中含有大量的铁。在此之前，我们建立了一个铁诱导的腹膜间皮瘤的大鼠模型，反复腹腔注射蔗糖铁和铁螯合剂，氨三乙酸。在这里，我们分析这些间皮瘤使用基于阵列的比较基因组杂交（aCGH）和基因表达谱微阵列。间皮瘤分为两个不同的类型后，病理评价免疫组化。主要类型为上皮样间皮瘤（EM），起源于图尼卡睾丸鞘膜附近，扩展到上腹膜腔，表现出乳头状生长和强烈的podoplanin免疫阳性。肉瘤样间皮瘤（sarcomatoid mesothelioma，SM）起源于腹腔内器官，具有显著的侵袭性和致死性。这两种类型的间皮瘤显示男性占优势。aCGH分析后，SM显示大量的基因组改变，包括CDKN 2A/2B纯合缺失和ERBB 2包含区域的扩增，而EM显示较少的基因组改变。尿调素在大多数病例中呈高表达。治疗4周后，观察到间皮膜中的铁沉积，并形成8-羟基-2'-脱氧鸟苷。这些结果不仅显示了铁诱导的腹膜间皮瘤的两种不同的分子途径，而且还支持了铁过载引起的氧化应激是CDKN2A/2B纯合缺失的主要原因的假设。
In humans, mesothelioma has been linked to asbestos exposure, especially crocidolite and amosite asbestos, which contain high amounts of iron. Previously, we established a rat model of iron-induced peritoneal mesothelioma with repeated intraperitoneal injections of iron saccharate and an iron chelator, nitrilotriacetate. Here, we analyze these mesotheliomas using array-based comparative genomic hybridization (aCGH) and gene expression profiling by micro-array. Mesotheliomas were classified into two distinct types after pathologic evaluation by immunohistochemistry. The major type, epithelioid mesothelioma (EM), originated in the vicinity of tunica vaginalis testis, expanded into the upper peritoneal cavity and exhibited papillary growth and intense podoplanin immunopositivity. The minor type, sarcomatoid mesothelioma (SM), originated from intraperitoneal organs and exhibited prominent invasiveness and lethality. Both mesothelioma types showed male preponderance. SMs revealed massive genomic alterations after aCGH analysis, including homozygous deletion of CDKN2A/2B and amplification of ERBB2 containing region, whereas EMs showed less genomic alterations. Uromodulin was highly expressed in most of the cases. After 4-week treatment, iron deposition in the mesothelia was observed with 8-hydroxy-2'-deoxyguanosine formation. These results not only show two distinct molecular pathways for iron-induced peritoneal mesothelioma, but also support the hypothesis that oxidative stress by iron overload is a major cause of CDKN2A/2B homozygous deletion.