Département Biologie du Cancer, Institut National de la Santé et de la Recherche Médicale, Institut de Génétique et de Biologie Moléculaire et Cellulaire, U964 Illkirch, France.
PLoS One. 2010 Jan 29;5(1):e8960. doi: 10.1371/journal.pone.0008960.
Squamous cell carcinoma (SCC) of the lung is a frequent and aggressive cancer type. Gene amplifications, a known activating mechanism of oncogenes, target the 3q26-qter region as one of the most frequently gained/amplified genomic sites in SCC of various types. Here, we used array comparative genomic hybridization to delineate the consensus region of 3q26.3 amplifications in lung SCC. Recurrent amplifications occur in 20% of lung SCC (136 tumors in total) and map to a core region of 2 Mb (Megabases) that encompasses SOX2, a transcription factor gene. Intense SOX2 immunostaining is frequent in nuclei of lung SCC, indicating potential active transcriptional regulation by SOX2. Analyses of the transcriptome of lung SCC, SOX2-overexpressing lung epithelial cells and embryonic stem cells (ESCs) reveal that SOX2 contributes to activate ESC-like phenotypes and provide clues pertaining to the deregulated genes involved in the malignant phenotype. In cell culture experiments, overexpression of SOX2 stimulates cellular migration and anchorage-independent growth while SOX2 knockdown impairs cell growth. Finally, SOX2 over-expression in non-tumorigenic human lung bronchial epithelial cells is tumorigenic in immunocompromised mice. These results indicate that the SOX2 transcription factor, a major regulator of stem cell function, is also an oncogene and a driver gene for the recurrent 3q26.33 amplifications in lung SCC.
肺鳞状细胞癌 (SCC) 是一种常见且侵袭性强的癌症类型。基因扩增是一种已知的致癌基因激活机制，其靶向 3q26-qter 区域，是各种类型 SCC 中最常获得/扩增的基因组位点之一。在这里，我们使用阵列比较基因组杂交技术来描绘肺 SCC 中 3q26.3 扩增的共识区域。肺 SCC 中反复出现的扩增发生在 20%的病例中（总共 136 个肿瘤），并映射到包含转录因子基因 SOX2 的 2Mb（兆碱基）核心区域。肺 SCC 细胞核中 SOX2 的免疫染色强烈，表明 SOX2 可能通过转录调控发挥作用。对肺 SCC、SOX2 过表达的肺上皮细胞和胚胎干细胞 (ESC) 的转录组分析表明，SOX2 有助于激活 ESC 样表型，并为涉及恶性表型的失调基因提供线索。在细胞培养实验中，SOX2 的过表达刺激细胞迁移和非锚定依赖性生长，而 SOX2 的敲低则会损害细胞生长。最后，SOX2 在非致瘤性人肺支气管上皮细胞中的过表达在免疫功能低下的小鼠中具有致瘤性。这些结果表明，SOX2 转录因子作为干细胞功能的主要调节因子，也是肺 SCC 中反复出现的 3q26.33 扩增的致癌基因和驱动基因。
