Relaxin Enhances S100A4 and Promotes Growth of Human Thyroid Carcinoma Cell Xenografts
Relaxin Enhances S100A4 and Promotes Growth of Human Thyroid Carcinoma Cell Xenografts
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DOI：
10.1158/1541-7786.mcr-09-0307
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发表时间：
2010-04-01
影响因子：
5.2
通讯作者：
Hombach-Klonisch, Sabine
中科院分区：
文献类型：
--
作者：
Radestock, Yvonne;Willing, Cornelia;Hombach-Klonisch, Sabine
松弛素能增加人甲状腺癌细胞的运动能力和体外侵袭力，但其潜在的分子机制尚不清楚。在本研究中，我们发现松弛素在转录水平上上调了钙结合蛋白S100A4(转移蛋白)，并增加了细胞内S100A4的10 kDa单体和20 kDa二聚体形式。当使用S100A4小干扰RNA敲除方法抑制S100A4的表达时，松弛素诱导的细胞运动增加被完全阻断。我们以前已经证明胰岛素样家族成员松弛素在人甲状腺癌组织中表达，但在良性甲状腺组织中不表达。表达松弛蛋白的人甲状腺癌组织也呈S100A4阳性。在裸鼠实验中，组成性表达松弛蛋白的人甲状腺癌细胞产生了巨大而快速生长的肿瘤，其增殖细胞数量显著增加。我们在我们的细胞模型中提供了证据，证明甲状腺癌转基因细胞分泌的松弛素靶蛋白S100A4不仅可以增强肿瘤细胞的运动能力，而且还可以促进异种移植血管的生成，这是由S100A4较高的肿瘤微血管密度和体外血管形成实验确定的。综上所述，我们已确定S100A4是松弛素在甲状腺癌细胞运动和体内甲状腺肿瘤血管生成中作用的主要介导物。摩尔癌症资源；8(4)；494-506。(C)2010年AACR。
Relaxin increases cell motility and in vitro invasiveness in human thyroid carcinoma cells but the underlying molecular mechanisms of this action are largely unknown. In the present study, we show that relaxin transcriptionally upregulates the calcium-binding protein S100A4 (metastasin) and increases the cytosolic 10-kDa monomer and the 20-kDa dimer form of S100A4 in human thyroid carcinoma cells. The relaxin-induced increase in cell motility was blocked completely when S100A4 expression was diminished using an S100A4 small interfering RNA knockdown approach. We have shown previously the expression of the insulin-like family member relaxin in human thyroid carcinoma tissues but not in benign thyroid tissues. Human thyroid carcinoma tissues expressing relaxin also stained positive for S100A4. In nude mouse experiments, human thyroid carcinoma cell transfectants with constitutive expression of relaxin generated large and fast-growing tumors with significantly increased numbers of proliferating cells. We provide evidence in our cell model that the relaxin target protein S100A4 secreted by the thyroid carcinoma transfectants may not only enhance tumor cell motility but also promote xenograft angiogenesis as determined by the higher density of tumor microvessels and the angiogenic potential of S100A4 in in vitro tube formation assays. In conclusion, we have identified S100A4 as a major mediator of the actions of relaxin in thyroid carcinoma cell motility and in vivo thyroid tumor angiogenesis. Mol Cancer Res; 8(4); 494-506. (C) 2010 AACR.