文章：

胚胎干细胞转录因子Sox2在ALK阳性间变性大细胞淋巴瘤中的异常表达及其生物学意义

Aberrant expression and biological significance of Sox2, an embryonic stem cell transcriptional factor, in ALK-positive anaplastic large cell lymphoma

原文发布日期：2012-08-10

DOI: 10.1038/bcj.2012.27

类型: Original Article

开放获取: 是

英文摘要：

Sox2 (sex-determining region Y-Box) is one of the master transcriptional factors that are important in maintaining the pluripotency of embryonic stem cells (ESCs). In line with this function, Sox2 expression is largely restricted to ESCs and somatic stem cells. We report that Sox2 is expressed in cell lines and tumor samples derived from ALK-positive anaplastic large cell lymphoma (ALK+ALCL), for which the normal cellular counterpart is believed to be mature T-cells. The expression of Sox2 in ALK+ALCL can be attributed to nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), the oncogenic fusion protein carrying a central pathogenetic role in these tumors. By confocal microscopy, Sox2 protein was detectable in virtually all cells in ALK+ALCL cell lines. However, the transcriptional activity of Sox2, as assessed using a Sox2-responsive reporter construct, was detectable only in a small proportion of cells. Importantly, downregulation of Sox2 using short interfering RNA in isolated Sox2active cells, but not Sox2inactive cells, resulted in a significant decrease in cell growth, invasiveness and tumorigenicity. To conclude, ALK+ALCL represents the first example of a hematologic malignancy that aberrantly expresses Sox2, which represents a novel mechanism by which NPM-ALK mediates tumorigenesis. We also found that the transcriptional activity and oncogenic effects of Sox2 can be heterogeneous in cancer cells.

摘要翻译： 

Sox2（Y框性别决定区）是维持胚胎干细胞多能性的关键转录调控因子之一。与此功能一致，Sox2的表达主要局限于胚胎干细胞和体干细胞。本研究发现，在ALK阳性间变性大细胞淋巴瘤（ALK+ALCL）的细胞系及肿瘤样本中存在Sox2表达，而该肿瘤对应的正常细胞被认为是成熟T细胞。Sox2在ALK+ALCL中的表达可归因于核磷蛋白-间变性淋巴瘤激酶（NPM-ALK）——在该类肿瘤中起核心致病作用的致癌融合蛋白。通过共聚焦显微镜观察，在ALK+ALCL细胞系中几乎所有细胞均能检测到Sox2蛋白。然而，采用Sox2响应报告基因载体进行评估时，仅在小部分细胞中检测到Sox2的转录活性。重要的是，在分离的Sox2活性细胞（而非非活性细胞）中使用短干扰RNA下调Sox2表达，可显著抑制细胞生长、侵袭能力和成瘤性。综上，ALK+ALCL是首例异常表达Sox2的血液系统恶性肿瘤，这揭示了NPM-ALK介导肿瘤发生的新机制。我们还发现，Sox2的转录活性和致癌效应在癌细胞中可能具有异质性。

原文链接：

Aberrant expression and biological significance of Sox2, an embryonic stem cell transcriptional factor, in ALK-positive anaplastic large cell lymphoma