Genes and Cancer Group, Cancer Epigenetics and Biology Program, PEBC, Bellvitge Biomedical Research Institute-IDIBELL, Barcelona, Spain.
Cancer Res. 2012 Jan 1;72(1):176-86. doi: 10.1158/0008-5472.CAN-11-3506. Epub 2011 Nov 14.
The HMG box transcription factor SOX4 involved in neuronal development is amplified and overexpressed in a subset of lung cancers, suggesting that it may be a driver oncogene. In this study, we sought to develop this hypothesis including by defining targets of SOX4 that may mediate its involvement in lung cancer. Ablating SOX4 expression in SOX4-amplified lung cancer cells revealed a gene expression signature that included genes involved in neuronal development such as PCDHB, MYB, RBP1, and TEAD2. Direct recruitment of SOX4 to gene promoters was associated with their upregulation upon ectopic overexpression of SOX4. We confirmed upregulation of the SOX4 expression signature in a panel of primary lung tumors, validating their specific response by a comparison using embryonic fibroblasts from Sox4-deficient mice. Interestingly, we found that small cell lung cancer (SCLC), a subtype of lung cancer with neuroendocrine characteristics, was generally characterized by high levels of SOX2, SOX4, and SOX11 along with the SOX4-specific gene expression signature identified. Taken together, our findings identify a functional role for SOX genes in SCLC, particularly for SOX4 and several novel targets defined in this study.
参与神经元发育的 HMG 盒转录因子 SOX4 在肺癌的一个亚群中被扩增和过表达，这表明它可能是一种驱动致癌基因。在这项研究中，我们试图通过确定 SOX4 的靶标来验证这一假说，这些靶标可能介导其在肺癌中的作用。在 SOX4 扩增的肺癌细胞中敲除 SOX4 表达，揭示了一个基因表达谱，其中包括参与神经元发育的基因，如 PCDHB、MYB、RBP1 和 TEAD2。SOX4 直接募集到基因启动子与它们在外源过表达 SOX4 时的上调有关。我们在一组原发性肺肿瘤中证实了 SOX4 表达谱的上调，通过使用 Sox4 缺陷型小鼠的胚胎成纤维细胞进行比较，验证了它们的特异性反应。有趣的是，我们发现具有神经内分泌特征的小细胞肺癌（SCLC）通常具有高水平的 SOX2、SOX4 和 SOX11，以及我们在此研究中确定的 SOX4 特异性基因表达谱。总之，我们的研究结果表明 SOX 基因在 SCLC 中具有功能作用，特别是 SOX4 和本研究中定义的几个新靶标。
