Université Libre de Bruxelles, IRIBHM, Brussels 1070, Belgium.
Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, Brussels 1070, Belgium.
Cell Stem Cell. 2015 Jul 2;17(1):60-73. doi: 10.1016/j.stem.2015.05.008. Epub 2015 Jun 18.
Sox9 is a transcription factor expressed in most solid tumors. However, the molecular mechanisms underlying Sox9 function during tumorigenesis remain unclear. Here, using a genetic mouse model of basal cell carcinoma (BCC), the most frequent cancer in humans, we show that Sox9 is expressed from the earliest step of tumor formation in a Wnt/β-catenin-dependent manner. Deletion of Sox9 together with the constitutive activation of Hedgehog signaling completely prevents BCC formation and leads to a progressive loss of oncogene-expressing cells. Transcriptional profiling of oncogene-expressing cells with Sox9 deletion, combined with in vivo ChIP sequencing, uncovers a cancer-specific gene network regulated by Sox9 that promotes stemness, extracellular matrix deposition, and cytoskeleton remodeling while repressing epidermal differentiation. Our study identifies the molecular mechanisms regulated by Sox9 that link tumor initiation and invasion.
Sox9 是一种在大多数实体瘤中表达的转录因子。然而， Sox9 在肿瘤发生过程中的功能的分子机制尚不清楚。在这里，我们使用基底细胞癌（BCC）的遗传小鼠模型，这是人类最常见的癌症，表明 Sox9 以 Wnt/β-catenin 依赖的方式在肿瘤形成的最早阶段表达。 Sox9 的缺失与 Hedgehog 信号的组成性激活一起，完全阻止了 BCC 的形成，并导致表达致癌基因的细胞逐渐丧失。 Sox9 缺失的表达致癌基因的细胞的转录谱，结合体内 ChIP 测序，揭示了 Sox9 调节的特定于癌症的基因网络，该网络促进了干性、细胞外基质沉积和细胞骨架重塑，同时抑制了表皮分化。我们的研究确定了 Sox9 调节的分子机制，这些机制将肿瘤起始和浸润联系起来。
