Aoyama Mineyoshi, Ozaki Toshinori, Inuzuka Hiroyuki, Tomotsune Daihachiro, Hirato Junko, Okamoto Yoshiaki, Tokita Hisashi, Ohira Miki, Nakagawara Akira
Division of Biochemistry, Chiba Cancer Center Research Institute, Japan.
Cancer Res. 2005 Jun 1;65(11):4587-97. doi: 10.1158/0008-5472.CAN-04-4630.
LIM-only proteins (LMO), which consist of LMO1, LMO2, LMO3, and LMO4, are involved in cell fate determination and differentiation during embryonic development. Accumulating evidence suggests that LMO1 and LMO2 act as oncogenic proteins in T-cell acute lymphoblastic leukemia, whereas LMO4 has recently been implicated in the genesis of breast cancer. However, little is known about the role of LMO3 in either tumorigenesis or development. In the present study, we have identified LMO3 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. Immunoprecipitation and immunostaining experiments showed that LMO3 was associated with HEN2 in mammalian cell nucleus. Human neuroblastoma SH-SY5Y cells stably overexpressing LMO3 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 LMO3 and HEN2 was significantly associated with a poor prognosis in 87 primary neuroblastomas. These results suggest that the deregulated expression of neuronal-specific LMO3 and HEN2 contributes to the genesis and progression of human neuroblastoma in a lineage-specific manner.
仅含LIM结构域的蛋白质（LMO）由LMO1、LMO2、LMO3和LMO4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，LMO1和LMO2在T细胞急性淋巴细胞白血病中作为致癌蛋白发挥作用，而最近有研究表明LMO4与乳腺癌的发生有关。然而，关于LMO3在肿瘤发生或发育中的作用知之甚少。在本研究中，我们鉴定出LMO3和编码神经元碱性螺旋-环-螺旋蛋白的HEN2，它们在预后不良的神经母细胞瘤中的表达水平高于预后良好的肿瘤。免疫沉淀和免疫染色实验表明，LMO3在哺乳动物细胞核中与HEN2相关联。与对照转染细胞相比，稳定过表达LMO3的人神经母细胞瘤SH-SY5Y细胞的细胞生长显著增加，软琼脂培养基中的集落形成得到促进，并且在裸鼠中肿瘤生长迅速。更重要的是，LMO3和HEN2的表达增加与87例原发性神经母细胞瘤的预后不良显著相关。这些结果表明，神经元特异性LMO3和HEN2的表达失调以谱系特异性方式促进了人类神经母细胞瘤的发生和进展。
