LMO3 interacts with neuronal transcription factor, HEN2, and acts as an oncogene in neuroblastoma
LMO3 interacts with neuronal transcription factor, HEN2, and acts as an oncogene in neuroblastoma
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DOI：
10.1158/0008-5472.can-04-4630
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发表时间：
2005-06-01
期刊：
影响因子：
11.2
通讯作者：
Nakagawara, A
中科院分区：
文献类型：
--
作者：
Aoyama, M;Ozaki, T;Nakagawara, A
LIM-only蛋白（LMO）由LM 01、LM 02、LM 03和LM 04组成，在胚胎发育过程中参与细胞命运的决定和分化。越来越多的证据表明LM 01和LM 02在T细胞急性淋巴细胞白血病中作为致癌蛋白，而LM 04最近被认为与乳腺癌的发生有关。然而，关于LM 03在肿瘤发生或发展中的作用知之甚少。在本研究中，我们已经确定了LM 03和HEN 2，它编码一个神经元的基本螺旋-环-螺旋蛋白，作为基因的表达水平较高，不利的神经母细胞瘤相比，那些有利的肿瘤。免疫沉淀和免疫染色实验表明，在哺乳动物细胞核中，LM 03与HEN 2结合。稳定过表达LM 03的人神经母细胞瘤SH-SY 5 Y细胞与对照转染子相比，显示出细胞生长的显著增加，在软琼脂培养基中促进集落形成，以及在裸鼠中的快速肿瘤生长。更重要的是，在87例原发性神经母细胞瘤中，LM 03和HEN 2的表达增加与预后不良显著相关。这些结果表明，神经元特异性LM 03和HEN 2的表达失调以谱系特异性方式促进人神经母细胞瘤的发生和发展。
LIM-only proteins (LMO), which consist of LM01, LM02, LM03, and LM04, are involved in cell fate determination and differentiation during embryonic development. Accumulating evidence suggests that LM01 and LM02 act as oncogenic proteins in T-cell acute lymphoblastic leukemia, whereas LM04 has recently been implicated in the genesis of breast cancer. However, little is known about the role of LM03 in either tumorigenesis or development. In the present study, we have identified LM03 and HEN2, which encodes a neuronal basic helix-loop-helix protein, as genes whose expression levels were higher in unfavorable neuroblastomas compared with those of favorable tumors. Inummoprecipitation and immunostaining experiments showed that LM03 was associated with HEN2 in mammalian cell nucleus. Human neuroblastoma SH-SY5Y cells stably overexpressing LM03 showed a marked increase in cell growth, a promotion of colony formation in soft agar medium, and a rapid tumor growth in nude mice compared with the control transfectants. More importantly, the increased expression of LM03 and HEN2 was significantly associated with a poor prognosis in 87 primary neuroblastomas. These results suggest that the deregulated expression of neuronal-specific LM03 and HEN2 contributes to the genesis and progression of human neuroblastoma in a lineage-specific manner.