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首页> 美国卫生研究院文献>Molecular Medicine >Derepression of HMGA2 Gene Expression in Retinoblastoma Is Associated with Cell Proliferation
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Derepression of HMGA2 Gene Expression in Retinoblastoma Is Associated with Cell Proliferation

机译：视网膜母细胞瘤中HMGA2基因表达的抑制与细胞增殖有关。

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To assess whether retinoblastoma formation is associated with the expression of high mobility group (HMG) A2 protein, a transcription factor that is highly expressed during embryogenesis and completely repressed in normal adult tissues, we performed Northern and Western blots and RT-PCR analyses, and immunohistochemistry to test for HMGA2 expression. We used established retinoblastoma cell lines in tumors grown in nude mice and clinical retinoblastoma specimens, and contrasted these tumors with normal embryonic and adult retina. Adenoviral-mediated antisense experiments were conducted on the retinoblastoma cell lines to suppress HMGA2 expression and determine if cell proliferation is HMGA2-dependent. We also transfected a retinoblastoma cell line to identify cis-regulatory elements and transcription initiation sites on the HMGA2 gene promoter. HMGA2 gene expression was silenced in terminally differentiated retina of 6-wk-old mice, but it was detected in retina of a 13.5-d postcoitum embryo. Reactivation of HMGA2 gene expression was observed in the retinoblastoma cell lines Y79, WERI-Rb1, and TOTL-1, in tumors derived from some of these cells propagated in nude mice, and in a high frequency of retinoblastomas excised from human patients. This suggests that expression of HMGA2 gene in retinoblastoma cells involves a derepression process. By using an antisense approach to block HMGA2 expression, we observed a decrease in the number of proliferating retinoblastoma cells. As a 1st step toward understanding HMGA2 gene reactivation in retinoblastoma, we mapped the 2 transcription initiation sites and associated positive regulatory elements within the WERI-Rb1 cells. Our discovery of derepression of HMGA2 gene expression in retinoblastoma provides the 1st evidence that this protein might contribute to neoplastic transformation of retina cells.
机译：为了评估视网膜母细胞瘤的形成是否与高迁移率族（HMG）A2蛋白的表达有关，HMG A2蛋白是在胚​​胎发生过程中高表达并在正常成人组织中被完全抑制的转录因子，我们进行了Northern和Western印迹和RT-PCR分析，以及免疫组化测试HMGA2表达。我们在裸鼠和临床视网膜母细胞瘤标本中生长的肿瘤中使用了已建立的视网膜母细胞瘤细胞系，并将这些肿瘤与正常的胚胎和成年视网膜进行了对比。在视网膜母细胞瘤细胞系上进行了腺病毒介导的反义实验，以抑制HMGA2的表达并确定细胞增殖是否为HMGA2依赖性的。我们还转染了视网膜母细胞瘤细胞系，以识别HMGA2基因启动子上的顺式调控元件和转录起始位点。 HMGA2基因表达在6周龄小鼠的终末分化视网膜中沉默，但在13.5天后宫腔胚胎的视网膜中被检测到。在视网膜母细胞瘤细胞系Y79，WERI-Rb1和TOTL-1中，在其中一些衍生自裸鼠的细胞中产生的肿瘤中，以及从人类患者中切除的视网膜母细胞瘤的高频率中，均观察到HMGA2基因表达的激活。这表明HMGA2基因在成视网膜细胞瘤细胞中的表达涉及抑制过程。通过使用反义方法来阻止HMGA2表达，我们观察到了增殖性视网膜母细胞瘤细胞数量的减少。作为了解视网膜母细胞瘤中HMGA2基因激活的第一步，我们在WERI-Rb1细胞内绘制了2个转录起始位点和相关的正调控元件。我们在视网膜母细胞瘤中发现HMGA2基因表达抑制的发现提供了第一个证据，证明该蛋白可能有助于视网膜细胞的肿瘤转化。

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