PNAS:科学家在高转移性肺癌细胞中发现重要分子
2016/6/14 0:32:27PNAS 世界医疗科技资讯

    

     来自美国费城Fox Chase癌症中心的研究人员在国际学术期刊PNAS上在线发表了一项最新研究进展，他们通过筛选找到了一个参与非小细胞肺癌侵袭转移的重要分子，同时也为预测该疾病的恶性程度提供了一个潜在的生物标记物。

     非小细胞肺癌(NSCLC)病人的5年生存率大约为16%，大多数病人死于无法控制的癌症转移。在这项最新研究中，研究人员对具有高转移能力和低转移能力的非小细胞肺癌细胞进行了筛选，着重寻找与干细胞特性相关的基因。经过筛选研究人员在转移能力较强的癌细胞中发现一种叫做Musashi-2(MSI2)的mRNA翻译调控因子的表达存在升高。随后研究人员又在非小细胞肺癌病人的肿瘤样本和正常肺组织中检测了MSI2的表达，发现MSI2在肿瘤样本中存在过表达的情况，并且MSI2的表达程度与疾病进展存在相关性。

     为了进一步验证MSI2表达与非小细胞非癌转移之间的关系，研究人员在小鼠模型和人类非小细胞非癌细胞系上删除了MSI2基因，结果发现癌细胞的侵袭能力和转移能力都出现了下降，并且这种现象并不依赖于癌细胞的增殖。删除MSI2基因能够显著地诱导与上皮细胞特性有关的蛋白表达，其中包括一些紧密连接蛋白如CLDN3，CLDN5和CLDN7，而一些与上皮间充质转化相关的基因则出现了表达下调，其中包括TGFβR1，SMAD3以及SNAIL和SLUG。在所有发生表达变化的基因中，研究人员发现过表达TGFβR1能够逆转删除MSI2基因导致的侵袭能力下降，而过表达CLDN7则会抑制依赖MSI2的癌细胞侵袭。除此之外，研究人员还观察到删除MSI2能够抑制E-cadherin表达。

     基于这项工作，文章作者提出MSI2能够为TGFβR1/SMAD3信号途径提供重要支持，促进肺部腺癌发生转移侵袭，同时也为预测非小细胞肺癌的侵袭性提供了一个潜在的标记物。

     原文

     doi: 10.1073/pnas.1513616113

     Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis

     Alexander E. Kudinova,b, Alexander Denekaa,c, Anna S. Nikonovaa, Tim N. Becka,d, Young-Ho Ahne,f, Xin Liue, Cathleen F. Martinezg, Fred A. Schultzg, Samuel Reynoldsg, Dong-Hua Yanga,h, Kathy Q. Caia,b, Khaled M. Yaghmoura, Karmel A. Bakera, Brian L. Eglestona, Emmanuelle Nicolasa,h, Adaeze Chikwema,i, Gregory Andrianovc, Shelly Singha, Hossein Borghaeia,j, Ilya G. Serebriiskiia,c, Don L. Gibbonse, Jonathan M. Kuriee, Erica A. Golemisa,d,1, and Yanis Boumber

     Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ?16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of KrasLA1/+;P53R172HΔG/+(KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCLC tumor specimens versus normal lung, whereas higher expression was associated with disease progression in an independent set of matched normal/primary tumor/lymph node specimens. Depletion of MSI2 in multiple independent metastatic murine and human NSCLC cell lines reduced invasion and metastatic potential, independent of an effect on proliferation. MSI2 depletion significantly induced expression of proteins associated with epithelial identity, including tight junction proteins [claudin 3 (CLDN3), claudin 5 (CLDN5), and claudin 7 (CLDN7)] and down-regulated direct translational targets associated with epithelial-mesenchymal transition, including the TGF-β receptor 1 (TGFβR1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGFβRI reversed the loss of invasion associated with MSI2 depletion, whereas overexpression of CLDN7 inhibited MSI2-dependent invasion. Unexpectedly, MSI2 depletion reduced E-cadherin expression, reflecting a mixed epithelial-mesenchymal phenotype. Based on this work, we propose that MSI2 provides essential support for TGFβR1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.

    

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