Deficient TSC1/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex
Deficient TSC1/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex
复制标题
SOX9-骨桥蛋白-AKT信号级联的TSC1/TSC2复合物抑制缺陷会限制结节性硬化症中的肿瘤生长
DOI：
10.1093/hmg/ddw397
复制
发表时间：
2017-01-15
影响因子：
3.5
通讯作者：
Zha, Xiaojun
中科院分区：
文献类型：
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作者：
Jin, Fuquan;Jiang, Keguo;Zha, Xiaojun
多发性硬化症（TSC）是一种常染色体显性遗传病，以多器官良性肿瘤为特征。TSC 1/TSC 2复合物对哺乳动物/雷帕霉素机制靶点（mTOR）信号传导的抑制的破坏导致TSC。过度活跃的mTOR介导的AKT负反馈调节部分有助于TSC相关肿瘤的良性性质。在这项研究中，我们证明了骨桥蛋白（OPN）的TSC 2-null小鼠胚胎成纤维细胞（MEFs），大鼠子宫平滑肌瘤衍生的TSC 2-缺陷细胞，转基因小鼠TSC模型和临床样本中的TSC 1/TSC 2复合物的损失显着减少。TSC 1/TSC 2复合物上调OPN表达由转录因子SOX 9以mTOR非依赖性方式介导。此外，缺乏TSC 1/TSC 2复合物的OPN的消融有助于TSC细胞中AKT的失活。最后，OPN的丰度决定了细胞增殖和肿瘤发展的效力。因此，TSC 1/TSC 2复合物的缺失导致AKT的mTOR非依赖性抑制，至少部分通过下调SOX 9-OPN信号级联。我们认为，减少的SOX 9-OPN-AKT信号通路保护防止恶性肿瘤的发展TSC患者。
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder featured with multi-organ benign tumours. Disruption of TSC1/TSC2 complex suppression on mammalian/mechanistic target of rapamycin (mTOR) signalling causes TSC. Hyperactive mTOR-mediated negative feedback regulation of AKT partially contributes to the benign nature of TSC-associated tumours. In this study, we demonstrated that osteopontin (OPN) was dramatically reduced by loss of TSC1/TSC2 complex in Tsc2-null mouse embryonic fibroblasts (MEFs), rat uterine leiomyoma-derived Tsc2-deficient cells, genetically modified mouse TSC models, and clinical samples. TSC1/TSC2 complex upregulation of OPN expression is mediated by transcription factor SOX9 in an mTOR-independent manner. Moreover, ablation of OPN by deficient TSC1/TSC2 complex contributed to inactivation of AKT in TSC cells. Lastly, the abundance of OPN dictated the potency of cell proliferation and tumour development. Therefore, loss of TSC1/TSC2 complex led to mTOR-independent inhibition of AKT at least partially through downregulation of the SOX9-OPN signalling cascade. We suggest that the decreased SOX9-OPN-AKT signalling pathway safeguard against the development of malignant tumours in TSC patients.