A novel molecular pathway for Snail-dependent, SPARC-mediated invasion in non-small cell lung cancer pathogenesis.
A novel molecular pathway for Snail-dependent, SPARC-mediated invasion in non-small cell lung cancer pathogenesis.
复制标题
一种新型的分子途径，用于蜗牛依赖性，SPARC介导的浸润在非小细胞肺癌发病机理中。
DOI：
10.1158/1940-6207.capr-13-0263
复制
发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Dubinett SM
中科院分区：
文献类型：
--
作者：
Grant JL;Fishbein MC;Hong LS;Krysan K;Minna JD;Shay JW;Walser TC;Dubinett SM
肺癌分子发病机制的定义使研究人员能够更好地了解疾病的自然史，从而促进新的预防策略的发展。除了调节上皮-间质转化（EMT），转录因子Snail对基因表达产生全局影响。我们最近的研究表明，Snail在非小细胞肺癌（NSCLC）中上调，与预后不良相关，并促进体内肿瘤进展。在此，我们证明了Snail的过表达导致癌前病变模型和已建立的疾病模型以及原位肺癌组织中酸性和富含半胱氨酸的分泌蛋白（SHP）的上调。Snail过度表达导致体外增加的SPARC依赖性侵袭，表明NAP 12可能在肺癌进展中发挥作用。生物信息学分析表明，TGF-β、ERK 1/2和miR-29 b是Snail介导的TGF-β上调的潜在中间体。在Snail过表达后，TGF-β1配体和TGF-βR2均上调。用TGF-β1处理人支气管上皮细胞（HBEC）系并抑制TGF-β1 mRNA表达可调节TGF-β1的表达。MEK磷酸化的抑制下调了ERK。miR-29 b在Snail过表达细胞系中下调，而miR-29 b的过表达抑制了Snail表达。此外，miR-29 b在ERK抑制后上调，表明Snail依赖性途径，通过该途径Snail激活TGF-β和ERK信号导致miR-29 b下调和随后的miR-29 b上调。我们对Snail诱导的NSCLC表达途径的发现有助于NSCLC发病机制的定义。
Definition of the molecular pathogenesis of lung cancer allows investigators an enhanced understanding of the natural history of the disease, thus fostering development of new prevention strategies. In addition to regulating epithelial-to-mesenchymal transition (EMT), the transcription factor Snail exerts global effects on gene expression. Our recent studies reveal that Snail is upregulated in non-small cell lung cancer (NSCLC), is associated with poor prognosis, and promotes tumor progression in vivo. Herein, we demonstrate that overexpression of Snail leads to upregulation of Secreted Protein, Acidic and Rich in Cysteine (SPARC) in models of premalignancy and established disease, as well as in lung carcinoma tissues in situ. Snail overexpression leads to increased SPARC-dependent invasion in vitro, indicating that SPARC may play a role in lung cancer progression. Bioinformatic analysis implicates TGF-β, ERK1/2, and miR-29b as potential intermediaries in Snail-mediated upregulation of SPARC. Both the TGF-β1 ligand and TGF-βR2 are upregulated following Snail overexpression. Treatment of human bronchial epithelial cell (HBEC) lines with TGF-β1 and inhibition of TGF-β1 mRNA expression modulated SPARC expression. Inhibition of MEK phosphorylation downregulated SPARC. MiR-29b is downregulated in Snail overexpressing cell lines, while overexpression of miR-29b inhibited SPARC expression. In addition, miR-29b was upregulated following ERK inhibition, suggesting a Snail-dependent pathway by which Snail activation of TGF-β and ERK signaling results in downregulation of miR-29b and subsequent upregulation of SPARC. Our discovery of pathways responsible for Snail-induced SPARC expression contributes to the definition of NSCLC pathogenesis.