Identification of the benign mesenchymal tumor gene HMGA2 in lymphangiomyomatosis
Identification of the benign mesenchymal tumor gene HMGA2 in lymphangiomyomatosis
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DOI：
10.1158/0008-5472.can-06-1122
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Chada, Kiran
中科院分区：
文献类型：
--
作者：
D'Armiento, Jeanine;Imai, Kazushi;Chada, Kiran
HMGA2是一种结构性转录因子，其正常表达模式主要局限于器官发生过程中明显分化之前的发育间充质细胞。详细的原位杂交分析表明，未分化的中胚层的胚胎肺表达Hmga 2，但它不表达在新生儿或成人肺。以前，HMGA2被证明是错误表达在一些良性的，分化的间叶肿瘤，包括脂肪瘤，子宫平滑肌瘤，肺软骨样错构瘤。在这里，我们发现HMGA 2在肺淋巴管肌瘤病（LAM）中错误表达，LAM是一种病因不明的严重疾病，由淋巴管平滑肌细胞增殖组成，导致气道、支气管和血管阻塞。用HMGA2抗体进行免疫组织化学，结果显示在21例LAM患者的肺组织样本中有表达。相反，HMGA 2在正常成人肺或其他增生性间质性肺病的切片中不表达，表明LAM中HMGA 2的表达代表异常的基因激活，而不仅仅是由于细胞增殖的增加。转基因小鼠体内研究表明，平滑肌细胞中HMGA 2的错误表达导致肺上皮细胞周围这些细胞的增殖增加。因此，类似于其他间充质肿瘤，HMGA 2在平滑肌细胞中的错误表达导致异常增殖和LAM肿瘤发生。这些结果表明，HMGA 2在LAM的发病机制中起着核心作用，并且是作为治疗靶点的潜在候选者。
The normal expression pattern of HMGA2, an architectural transcription factor, is primarily restricted to cells of the developing mesenchyme before their overt differentiation during organogenesis. A detailed in situ hybridization analysis showed that the undifferentiated mesoderm of the embryonic lung expressed Hmga2 but it was not expressed in the newborn or adult lung. Previously, HMGA2 was shown to be misexpressed in a number of benign, differentiated mesenchymal tumors including lipomas, uterine leiomyomas, and pulmonary chondroid hamartomas. Here, we show that HMGA2 is misexpressed in pulmonary lymphangiomyomatosis (LAM), a severe disorder of unknown etiology consisting of lymphatic smooth muscle cell proliferation that results in the obstruction of airways, lymphatics, and vessels. Immunohistochemistry was done with antibodies to HMGA2 and revealed expression in lung tissue samples obtained from 21 patients with LAM. In contrast, HMGA2 was not expressed in sections of normal adult lung or other proliferative interstitial lung diseases, indicating that the expression of HMGA2 in LAM represents aberrant gene activation and is not due solely to an increase in cellular proliferation. In vivo studies in transgenic mice show that misexpression of HMGA2 in smooth muscle cells resulted in increased proliferation of these cells in the lung surrounding the epithelial cells. Therefore, similar to the other mesenchymal neoplasms, HMGA2 misexpression in the smooth muscle cell leads to abnormal proliferation and LAM tumorigenesis. These results suggest that HMGA2 plays a central role in the pathogenesis of LAM and is a potential candidate as a therapeutic target.