Identification of S100A14 as a metastasis-promoting molecule in a murine organotropic metastasis model
Identification of S100A14 as a metastasis-promoting molecule in a murine organotropic metastasis model
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DOI：
10.1007/s10585-019-09979-w
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发表时间：
2019-08-01
影响因子：
4
通讯作者：
Akiyama, Yasuto
中科院分区：
文献类型：
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作者：
Sugino, Takashi;Ichikawa-Tomikawa, Naoki;Akiyama, Yasuto
肿瘤转移在靶器官、转移途径和分子机制上表现出很大的多样性，这取决于癌症的类型，甚至取决于患者的个体。为了确定参与转移的关键分子，我们构建了一个小鼠模型系统，包括多个具有不同器官趋向性和转移途径的亚系。我们从小鼠乳腺肿瘤细胞系MCH66中选择了转移的亚系。利用该模型，我们通过基因表达筛选的方法提取转移相关分子，并通过基因敲除或过表达实验验证其促进转移的作用。对于促进转移的候选细胞，我们分析了与转移相关的分子功能：细胞生长、运动和侵袭活性。我们建立了一种包括低转移亚系(66C8、66LM、66-4)和高转移亚系(如肺(66L-10)、肝(HM-KAN5)和全身器官(66HM及其克隆：HM1-6和HM1-7))的转移模型。66HM和HM-KAN5亚系基本表现为以内皮细胞覆盖的癌栓为特征的非侵袭非侵袭转移途径，而66HM和HM-KAN5则分别表现为部分和全部侵袭的选择性转移途径。综合基因分析提取了几个与转移有关的候选分子。经体内基因敲除实验证实，S100A14是有希望促进肺转移的候选基因之一。此外，体内和体外功能分析表明，S100A14增强了小鼠肿瘤细胞的散射性、运动性和侵袭性。我们的模型系统可能适用于人类肿瘤转移的多样性，并有助于探索转移的分子机制。
Cancer metastasis shows great diversity in target organs, routes and molecular mechanisms depending on the type of cancer and even on the individual patients. To identify key molecules involved in metastasis, we constructed a murine model system including multiple sublines with different organotropism and pathways of metastasis. We selected metastatic sublines from a murine mammary tumor cell line MCH66. Using this model, we extracted metastasis-related molecules by gene expression screening methods and verified their metastasis-promoting effects by gene knockdown or overexpression experiments. For the candidates promoting metastasis, we analyzed molecular functions involved in metastasis: cell growth, motility and invasive activity. We established a metastasis model including low metastatic sublines (66C8, 66LM, 66-4) and highly metastatic counterparts with various organotropism, such as to the lung (66L-10), liver (HM-KAN5) and general organs (66HM and its clones: HM1-6 and HM1-7). The sublines basically exhibited the invasion-independent metastasis pathway characterized by endothelial cell-covered tumor emboli, whereas 66HM and HM-KAN5 showed an alternative metastasis pathway based on invasion in part and in whole, respectively. Comprehensive gene analysis extracted several molecular candidates responsible for metastasis. S100A14 was identified as one of the promissing candidates promoting lung-metastasis, which was verified by gene knockdown experiments in vivo. In addition, in vivo and in vitro functional analyses demonstrated that S100A14 enhanced scattering, motility and invasiveness of mouse tumor cells. Our model system may be adaptable to the diversity of metastasis in human cancers and useful for exploring the molecular mechanism responsible for metastasis.