SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma
SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma
复制标题
DOI：
10.1038/nature13305
复制
发表时间：
2014-07-10
期刊：
影响因子：
64.8
通讯作者：
Blanpain, Cedric
中科院分区：
文献类型：
--
作者：
Boumahdi, Soufiane;Driessens, Gregory;Blanpain, Cedric
癌症干细胞（CSC）已在各种癌症中报道，包括皮肤鳞状细胞癌（SCC）（1-4）。调节肿瘤发生和干性的分子机制仍然缺乏特征。在此，我们发现Sox 2是一种在各种类型的胚胎和成体干细胞中表达的转录因子（5，6），是小鼠鳞状皮肤肿瘤CSC中上调最多的转录因子。SOX 2在正常表皮中不存在，但在绝大多数小鼠和人肿瘤前皮肤肿瘤中开始表达，并且在侵袭性小鼠和人SCC中继续以异质方式表达。与其他SCC相比，其中SOX 2经常被遗传扩增（7），小鼠和人皮肤SCC中SOX 2的表达受到转录调节。小鼠表皮中Sox 2的条件性缺失显着降低化学诱导致癌后皮肤肿瘤的形成。使用绿色荧光蛋白（GFP）作为Sox 2转录表达的报告基因（SOX 2-GFP敲入小鼠），我们发现侵袭性SCC中的SOX 2表达细胞在肿瘤增殖细胞中大量富集，在连续移植后进一步增加。原发性良性和恶性SCC中SOX 2表达细胞的谱系消融导致肿瘤消退，这与SOX 2表达细胞在肿瘤维持中的关键作用一致。预先存在的皮肤乳头状瘤和SCC中的条件性Sox 2缺失导致肿瘤消退，并降低癌细胞在移植到免疫缺陷小鼠中后繁殖的能力，支持Sox 2在调节CSC功能中的重要作用。表达SOX 2-GFP的CSC和Sox 2缺失后的肿瘤上皮细胞的转录谱分析揭示了在体内原发性肿瘤细胞中由SOX 2调节的基因网络。染色质免疫沉淀鉴定了几个直接的SOX 2靶基因控制肿瘤的干性，生存，增殖，粘附，侵袭和副肿瘤综合征。我们证明，SOX 2通过标记和调节皮肤肿瘤起始细胞和CSC的功能，在原发性皮肤肿瘤中建立了肿瘤起始和进展之间的连续体。
Cancer stem cells (CSCs) have been reported in various cancers, including in skin squamous-cell carcinoma (SCC)(1-4). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here we find that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells(5,6), was the most upregulated transcription factor in the CSCs of squamous skin tumours in mice. SOX2 is absent in normal epidermis but begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours, and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which SOX2 is frequently genetically amplified(7), the expression of SOX2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis markedly decreases skin tumour formation after chemical-induced carcinogenesis. Using green fluorescent protein (GFP) as a reporter of Sox2 transcriptional expression (SOX2-GFP knock-in mice), we showed that SOX2-expressing cells in invasive SCC are greatly enriched in tumour-propagating cells, which further increase upon serial transplantations. Lineage ablation of SOX2-expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of SOX2-expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to tumour regression and decreases the ability of cancer cells to be propagated upon transplantation into immunodeficient mice, supporting the essential role of SOX2 in regulating CSC functions. Transcriptional profiling of SOX2-GFP expressing CSCs and of tumour epithelial cells upon Sox2 deletion uncovered a gene network regulated by SOX2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct SOX2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion and paraneoplastic syndrome. We demonstrate that SOX2, by marking and regulating the functions of skin tumour-initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours.