Positive Feedback Loops Between NrCAM and Major Signaling Pathways Contribute to Thyroid Tumorigenesis
Positive Feedback Loops Between NrCAM and Major Signaling Pathways Contribute to Thyroid Tumorigenesis
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DOI：
10.1210/jc.2016-1677
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发表时间：
2016-10
期刊：
影响因子：
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通讯作者：
Yanfang Zhang;Fang Sui;Jingjing Ma;Xiaojuan Ren;H. Guan;Qi Yang;Jing Shi;Meiju Ji;B. Shi;Yue Sun;P. Hou
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文献类型：
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作者：
Yanfang Zhang;Fang Sui;Jingjing Ma;Xiaojuan Ren;H. Guan;Qi Yang;Jing Shi;Meiju Ji;B. Shi;Yue Sun;P. Hou
背景：尽管据报道神经元细胞粘附分子 (NrCAM) 在甲状腺乳头状癌 (PTC) 中过度表达，但其在这种疾病中的作用仍不清楚。目的：本研究的目的是探讨 NrCAM 的生物学功能及其作为甲状腺癌诊断标志物和治疗靶点的潜力。实验设计：进行定量实时聚合酶链式反应 (qRT-PCR) 以评估所研究基因的信使 RNA 表达。通过一系列体外和体内实验确定了甲状腺癌细胞中NrCAM的敲低和异位表达的功能。结果：我们发现 NrCAM 在 PTC 中高表达，证明 NrCAM 可能是 PTC 术前诊断的潜在标志物。此外，NrCAM 消耗显着抑制裸鼠中甲状腺癌细胞的生长、侵袭性和致瘤潜力。另一方面，NrCAM的异位表达显着增强了其促瘤作用。从机械角度来看，NrCAM 通过其胞外域脱落并与 EGFR 和 41 整合素结合，激活 MAPK/Erk 和 PI3K/Akt 通路，从而发挥其致癌功能。反过来，这两条途径也通过 GSK3/-catenin 信号轴在甲状腺癌细胞中导致 NrCAM 过度表达。在甲状腺特异性敲入致癌基因 BrafV600E (TPO-Cre/LSL-BrafV600E) 的转基因小鼠中也发现了类似的结果。结论：我们的数据首先揭示了 NrCAM 与通过调节肿瘤微环境促进甲状腺肿瘤发生的主要信号通路之间的正反馈环，并表明 NrCAM 可能代表甲状腺癌的潜在诊断标志物和治疗靶点。
Context: Although neuronal cell adhesion molecule (NrCAM) has been reported to be overexpressed in papillary thyroid cancer (PTCs), its role in this disease remains largely unclear. Objectives: The aim of this study was to explore the biological functions of NrCAM and its potential as a diagnostic marker and therapeutic target in thyroid cancer. Experimental Design: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate messenger RNA expression of investigated genes. The functions of knockdown and ectopic expression of NrCAM in thyroid cancer cells were determine by a series of in vitro and in vivo experiments. Results: We found that NrCAM was highly expressed in PTCs and demonstrated that NrCAM might be a potential marker for preoperative diagnosis of PTC. Moreover, NrCAM depletion dramatically inhibited thyroid cancer cell growth, invasiveness and tumorigenic potential in nude mice. On the other hand, ectopic expression of NrCAM significantly enhanced its tumor-promoting effects. Mechanically, NrCAM exerted its oncogenic function by activating MAPK/Erk and PI3K/Akt pathways via its ectodomain shedding and binding to EGFR and 41 integrins. In turn, these 2 pathways were also responsible for NrCAM overexpression through GSK3/-catenin signaling axis in thyroid cancer cells. Similar results were also found in transgenic mice with thyroid-specific knock-in of oncogenic BrafV600E (TPO-Cre/LSL-BrafV600E). Conclusions: Our data first reveal positive feedback loops between NrCAM and major signaling pathways contributing to thyroid tumorigenesis by modulating tumor microenvironment, and suggest that NrCAM may represent a potential diagnostic marker and therapeutic target for thyroid cancer.