An ADAM12 and FAK positive feedback loop amplifies the interaction signal of tumor cells with extracellular matrix to promote esophageal cancer metastasis
An ADAM12 and FAK positive feedback loop amplifies the interaction signal of tumor cells with extracellular matrix to promote esophageal cancer metastasis
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ADAM12和FAK正反馈环路放大肿瘤细胞与细胞外基质的相互作用信号，促进食管癌转移
DOI：
10.1016/j.canlet.2018.02.031
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Hu, Hai
中科院分区：
文献类型：
--
作者：
Luo, Man-Li;Zhou, Zhuan;Hu, Hai
食管鳞状细胞癌（ESCC）预后差，主要是由于早期转移。为了探讨食管鳞癌早期转移的机制，我们建立了一种模拟肿瘤细胞与细胞外基质相互作用的体外筛选模型，通过该模型获得了具有高侵袭能力的食管鳞癌细胞亚系。通过比较高侵袭性亚系与亲本细胞的基因表达谱，ADAM 12-L被鉴定为促进ESCC细胞侵袭的候选基因。免疫组化结果显示，ADAM 12-L在食管鳞癌组织中呈高表达，尤其是在癌组织的浸润边缘，且与食管鳞癌患者的转移和预后密切相关。事实上，ADAM 12-L敲低降低了体外和体内ESCC细胞的侵袭和转移。此外，我们还证实了ADAM 12-L参与了黏着斑的转换，并促进黏着斑激酶（FAK）的激活，进而通过FAK/JNK/c-Jun轴增加ADAM 12-L的转录。因此，在通过FAK和c-Jun与细胞外基质接合以增强ADAM 12-L表达时，建立了从癌细胞起始的环，导致进一步FAK活化的正反馈并促进转移。我们的研究表明，ADAM 12-L的过表达可以作为一个精确的标记，以确定该环的激活。靶向ADAM 12-L以破坏这种正反馈回路代表了治疗食管癌转移的有希望的策略。(C)2018 Elsevier B. V.版权所有。
Esophageal squamous cell carcinomas (ESCCs) have a poor prognosis mostly due to early metastasis. To explore the early event of metastasis in ESCC, we established an in vitro selection model to mimic the interaction of tumor cells with extracellular matrix, through which a sub-line of ESCC cells with high invasive ability was generated. By comparing the gene expression profile of the highly invasive sub-line to that of the parental cells, ADAM12-L was identified as a candidate gene promoting ESCC cell invasion. Immunohistochemistry revealed that the ADAM12-L was overexpressed in human ESCC tissues, especially at cancer invasive edge, and ADAM12-L overexpression tightly correlated with increased metastasis and poor outcome of ESCC patients. Indeed, ADAM12-L knockdown reduced the invasion and metastasis of ESCC cells both in vitro and in vivo. Furthermore, we demonstrated that ADAM12-L participated in focal adhesion turnover and promoted the activation of focal adhesion kinase (FAK), which in turn increased ADAM12-L transcription through FAK/JNK/c-Jun axis. Therefore, a loop initiated from the cancer cell upon the engagement with extracellular matrix through FAK and c-Jun to enhance ADAM12-L expression is established, leading to the positive feedback of further FAK activation and prompting metastasis. Our study indicates that overexpression of ADAM12-L can serve as a precision marker to determine the activation of this loop. Targeting ADAM12-L to disrupt this positive feedback loop represents a promising strategy to treat the metastasis of esophageal cancers. (C) 2018 Elsevier B.V. All rights reserved.