Baris Olivier, Savagner Frédérique, Nasser Valéry, Loriod Béatrice, Granjeaud Samuel, Guyetant Serge, Franc Brigitte, Rodien Patrice, Rohmer Vincent, Bertucci François, Birnbaum Daniel, Malthièry Yves, Reynier Pascal, Houlgatte Rémi
Institut National de la Santé et de la Recherche Médicale, Equipe Mixte INSERM-Universitaire 0018, Laboratoire de Biochimie et Biologie Moléculaire, Centre Hospitalier Universitaire, Angers F-49033, France.
J Clin Endocrinol Metab. 2004 Feb;89(2):994-1005. doi: 10.1210/jc.2003-031238.
Oncocytomas are large cell tumors characterized by an abnormal proliferation of mitochondria. To investigate this phenomenon in thyroid oncocytomas, we determined gene expression profiles of 87 samples using microarrays of 6720 PCR products from cDNA clones. Samples included 29 thyroid oncocytomas and six papillary carcinomas, the remainder representing other thyroid pathologies or mitochondria-rich tumor samples, normal thyroid samples, and two thyroid cell lines. Hierarchical clustering and supervised analysis identified two specific oncocytic clusters and 163 distinctly regulated genes between oncocytoma and normal thyroid. Differential expression of five selected genes (APOD, BCL-2, COX, CTSB, and MAP2) was confirmed by immunohistochemistry. The two specific oncocytic clusters were rich in mitochondrial genes and revealed coordinated expression of nuclear and mitochondrial respiratory chain genes. We also observed the up-regulation of genes involved in mitochondrial biogenesis, such as nuclear respiratory factor 1 and the endothelial nitric oxide synthase. Several oxidative metabolism genes were overexpressed in oncocytomas, including those from the tricarboxylic acid cycle (MDH1) and cytosolic glycolysis (GAPD, ENO1, and GPI). On the contrary, the lactate dehydrogenase A gene, involved in anaerobic metabolism, was down-regulated. Our results suggest that, unlike a large number of solid tumors, thyroid oncocytomas produce energy through an aerobic pathway.
嗜酸细胞瘤是一种以线粒体异常增殖为特征的大细胞肿瘤。为了研究甲状腺嗜酸细胞瘤中的这一现象，我们使用来自cDNA克隆的6720个PCR产物的微阵列，测定了87个样本的基因表达谱。样本包括29个甲状腺嗜酸细胞瘤和6个乳头状癌，其余样本代表其他甲状腺病变或富含线粒体的肿瘤样本、正常甲状腺样本以及两个甲状腺细胞系。层次聚类和监督分析确定了两个特定的嗜酸细胞簇，以及嗜酸细胞瘤和正常甲状腺之间163个明显调控的基因。通过免疫组织化学证实了五个选定基因（载脂蛋白D、B细胞淋巴瘤-2、细胞色素C氧化酶、组织蛋白酶B和微管相关蛋白2）的差异表达。这两个特定的嗜酸细胞簇富含线粒体基因，并显示出核呼吸链基因和线粒体呼吸链基因的协同表达。我们还观察到参与线粒体生物发生的基因上调，如核呼吸因子1和内皮型一氧化氮合酶。几种氧化代谢基因在嗜酸细胞瘤中过表达，包括三羧酸循环（苹果酸脱氢酶1）和胞质糖酵解（甘油醛-3-磷酸脱氢酶、烯醇化酶1和葡萄糖磷酸异构酶）中的基因。相反，参与无氧代谢的乳酸脱氢酶A基因下调。我们的结果表明，与大量实体瘤不同，甲状腺嗜酸细胞瘤通过有氧途径产生能量。
