Sox2 is required for tumor development and cancer cell proliferation in osteosarcoma.
Sox2 is required for tumor development and cancer cell proliferation in osteosarcoma.
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DOI：
10.1038/s41388-018-0292-2
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发表时间：
2018-08
期刊：
影响因子：
8
通讯作者：
Basilico C
中科院分区：
文献类型：
--
作者：
Maurizi G;Verma N;Gadi A;Mansukhani A;Basilico C
干细胞转录因子Sox2在许多癌症中高度表达，它被认为是癌症干细胞（CSC）的标志。在最常见的骨恶性肿瘤骨肉瘤中，Sox2的高表达标志并维持了一部分肿瘤起始细胞，这些细胞显示出CSC的所有特性。敲低Sox2表达可消除致瘤性并抑制CSC表型。本研究表明，在骨肉瘤小鼠模型中，成骨细胞特异性Sox2条件敲除（CKO）可显著降低肿瘤发生的频率和发生率。在Sox2 CKO动物中检测到的罕见肿瘤均为Sox2阳性，表明它们起源于逃避Sox2缺失的细胞。此外，通过CRISPR/CAS技术在培养的骨肉瘤细胞中使Sox2失活，导致整个细胞群的活力和增殖能力丧失。YAP基因是Hippo Pathway的主要效应因子，是Sox2的直接靶点，它的失活也会导致类似的结果，而YAP的过表达可以拯救Sox2失活导致的细胞死亡。这些影响是骨肉瘤特异性的，提示细胞对Sox2启动通路的“成瘾”机制。骨肉瘤的形成和肿瘤细胞的存活都需要Sox2，这表明破坏Sox2启动的通路可能是治疗骨肉瘤的一种有效策略。
The stem cell transcription factor Sox2 is highly expressed in many cancers where it is thought to mark cancer stem cells (CSC). In osteosarcomas, the most common bone malignancy, high Sox2 expression marks and maintains a fraction of tumor initiating cells that show all the properties of CSC. Knock down of Sox2 expression abolishes tumorigenicity and suppresses the CSC phenotype. Here we show that, in a mouse model of osteosarcoma, osteoblast-specific Sox2 conditional knockout (CKO) causes a drastic reduction in the frequency and onset of tumors. The rare tumors detected in the Sox2 CKO animals were all Sox2 positive, indicating that they arose from cells that had escaped Sox2 deletion. Furthermore Sox2 inactivation in cultured osteosarcoma cells by CRISPR/CAS technology leads to a loss of viability and proliferation of the entire cell population. Inactivation of the YAP gene, a major Hippo Pathway effector which is a direct Sox2 target, causes similar results and YAP overexpression rescues cells from the lethality caused by Sox2 inactivation. These effects were osteosarcoma-specific, suggesting a mechanism of cell “addiction” to Sox2 initiated pathways. The requirement for Sox2 for osteosarcoma formation as well as for the survival of the tumor cells suggests that disruption of Sox2-initiated pathways could be an effective strategy for the treatment of osteosarcoma.
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影响因子：
10.5
作者：
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通讯作者：
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影响因子：
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DOI：
10.1073/pnas.0805462105
发表时间：
2008-08-19
影响因子：
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作者：
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通讯作者：
Lees, Jacqueline A.
影响因子：
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作者：
Palumbo, Paola;Miconi, Gianfranca;Cifone, Maria Grazia
通讯作者：
Cifone, Maria Grazia