PAX3-NCOA2 fusion gene has a dual role in promoting the proliferation and inhibiting the myogenic differentiation of rhabdomyosarcoma cells
PAX3-NCOA2 fusion gene has a dual role in promoting the proliferation and inhibiting the myogenic differentiation of rhabdomyosarcoma cells
复制标题
PAX3-NCOA2融合基因具有促进横纹肌肉瘤细胞增殖和抑制成肌分化的双重作用
作者：
Yoshida H;Miyachi M;Hosoi H;et al
我们分析了一例胚胎横纹肌肉瘤（RMS）的复杂染色体易位，发现它产生了融合基因PAX3（配对框3）-NCOA2（核受体共激活因子2）。为了了解这种易位在RMS肿瘤发生中的作用，我们建立了两种稳定的小鼠成肌细胞C2C12细胞系，分别表达PAX3-NCOA2和PAX3-FOXO1A （forkhead box O1A）。与对照细胞相比，PAX3- ncoa2细胞生长更快，移动性更强，锚定依赖性更小，细胞周期G1/S期进展更快，PAX3共识结合位点的转录激活程度更高。然而，PAX3-NCOA2细胞比PAX3-FOXO1A细胞增殖更慢，分化更弱。PAX3-NCOA2细胞和PAX3-FOXO1A细胞在裸鼠体内均形成肿瘤，但PAX3-NCOA2诱导的肿瘤生长较慢。我们的研究结果可以解释为什么NCOA2重排主要发生在胚胎性横纹肌肉瘤中，胚胎性横纹肌肉瘤比表达PAX3-FOXO1A融合基因的肺泡性横纹肌肉瘤预后更好。这些结果表明PAX3-NCOA2融合基因在RMS的肿瘤发生中具有双重作用：促进RMS细胞的增殖和抑制RMS细胞的成肌分化。
We analyzed a complex chromosomal translocation in a case of embryonal rhabdomyosarcoma (RMS) and showed that it generates the fusion gene PAX3 (paired box 3)-NCOA2 (nuclear receptor coactivator 2). To understand the role of this translocation in RMS tumorigenesis, we established two types of stable mouse myoblast C2C12 cell lines expressing PAX3-NCOA2 and PAX3-FOXO1A (forkhead box O1A), respectively. Compared with control cells, PAX3-NCOA2 cells grew faster, were more motile, were less anchorage dependent, progressed more quickly through the G1/S phase of cell cycle and showed greater transcriptional activation of the PAX3 consensus-binding site. However, PAX3-NCOA2 cells proliferated more slowly and differentiated more weakly than did PAX3-FOXO1A cells. Both PAX3-NCOA2 cells and PAX3-FOXO1A cells formed tumors in nude mice, although the PAX3-NCOA2-induced tumors grew more slowly. Our results may explain why NCOA2 rearrangement is mainly found in embryonal rhabdomyosarcoma, which has a better prognosis than alveolar rhabdomyosarcoma, which expresses the PAX3-FOXO1A fusion gene. These results indicate that the PAX3-NCOA2 fusion gene has a dual role in the tumorigenesis of RMS: promotion of the proliferation and inhibition of the myogenic differentiation of RMS cells.