Regulation of VEGFR2 and AKT Signaling by Musashi-2 in Lung Cancer.
Regulation of VEGFR2 and AKT Signaling by Musashi-2 in Lung Cancer.
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肺癌是世界范围内最常见和最致命的恶性肿瘤。Musashi-2（MSI 2）是一种RNA结合蛋白，在晚期NSCLC中过表达。VEGFR 2蛋白表达有助于NSCLC进展，并且在临床中使用了几种FDA批准的药物来靶向它。在这里，我们表明，MSI 2是一个强大的正调控VEGFR 2蛋白水平在小鼠和人类NSCLC细胞系。此外，我们发现MSI 2蛋白直接与VEGFR 2和PTEN mRNA结合，并部分通过PTEN调节影响VEGFR 2下游信号传导。肺癌是最常见的癌症类型，也是全球癌症相关死亡的主要原因。非小细胞肺癌（NSCLC）代表了大多数肺癌的诊断。血管内皮生长因子受体-2（VEGFR 2）是受体酪氨酸激酶蛋白的VEGF家族的成员，其在内皮细胞和肿瘤细胞上表达，是促成癌症发展的关键蛋白之一，并且参与耐药性。我们先前发现Musashi-2（MSI 2）RNA结合蛋白通过调节与NSCLC相关的几种信号通路与NSCLC进展相关。在这项研究中，我们进行了反向蛋白质相位阵列（RPPA）分析小鼠肺癌，这表明，VEGFR 2蛋白是强烈的正调控MSI 2。接下来，我们在几种人肺腺癌细胞系模型中验证了MSI 2对VEGFR 2蛋白的调控。此外，我们发现MSI 2通过负性PTENmRNA翻译调节影响AKT信号传导。计算机模拟预测分析表明，VEGFR 2和PTEN mRNA都具有MSI 2的预测结合位点。我们接下来进行了RNA免疫沉淀结合定量PCR，这证实了MSI 2直接结合VEGFR 2和PTEN mRNA，表明了直接调节机制。最后，在人肺腺癌样本中，MSI 2表达与VEGFR 2和VEGF-A蛋白水平呈正相关。我们的结论是，MSI 2/VEGFR 2轴有助于肺腺癌的进展，值得进一步研究和治疗靶向。
Lung cancer is the most common and lethal malignancy worldwide. Musashi-2 (MSI2) is an RNA-binding protein that is overexpressed in advanced NSCLC. VEGFR2 protein expression contributes to NSCLC progression and several FDA-approved drugs are used to target it in the clinic. Here, we show that MSI2 is a strong positive regulator of VEGFR2 protein levels in murine and human NSCLC cell lines. Furthermore, we found that MSI2 protein directly binds to VEGFR2 and PTEN mRNAs and impacts VEGFR2 downstream signaling, in part via PTEN regulation. Lung cancer is the most frequently diagnosed cancer type and the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents most of the diagnoses of lung cancer. Vascular endothelial growth factor receptor-2 (VEGFR2) is a member of the VEGF family of receptor tyrosine kinase proteins, which are expressed on both endothelial and tumor cells, are one of the key proteins contributing to cancer development, and are involved in drug resistance. We previously showed that Musashi-2 (MSI2) RNA-binding protein is associated with NSCLC progression by regulating several signaling pathways relevant to NSCLC. In this study, we performed Reverse Protein Phase Array (RPPA) analysis of murine lung cancer, which suggests that VEGFR2 protein is strongly positively regulated by MSI2. Next, we validated VEGFR2 protein regulation by MSI2 in several human lung adenocarcinoma cell line models. Additionally, we found that MSI2 affected AKT signaling via negative PTEN mRNA translation regulation. In silico prediction analysis suggested that both VEGFR2 and PTEN mRNAs have predicted binding sites for MSI2. We next performed RNA immunoprecipitation coupled with quantitative PCR, which confirmed that MSI2 directly binds to VEGFR2 and PTEN mRNAs, suggesting a direct regulation mechanism. Finally, MSI2 expression positively correlated with VEGFR2 and VEGF-A protein levels in human lung adenocarcinoma samples. We conclude that the MSI2/VEGFR2 axis contributes to lung adenocarcinoma progression and is worth further investigations and therapeutic targeting.
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DOI：
10.1084/jem.20130736
发表时间：
2014-01-13
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Park SM;Deering RP;Lu Y;Tivnan P;Lianoglou S;Al-Shahrour F;Ebert BL;Hacohen N;Leslie C;Daley GQ;Lengner CJ;Kharas MG
通讯作者：
Kharas MG
影响因子：
45.3
作者：
Reckamp, Karen L.;Redman, Mary W.;Dragnev, Konstantin H.;Minichiello, Katherine;Villaruz, Liza C.;Faller, Bryan;Al Baghdadi, Tareq;Hines, Susan;Everhart, Leah;Highleyman, Louise;Papadimitrakopoulou, Vassiliki;Gandara, David R.;Kelly, Karen;Herbst, Roy S.
通讯作者：
Herbst, Roy S.
影响因子：
15.8
作者：
Lee TH;Seng S;Sekine M;Hinton C;Fu Y;Avraham HK;Avraham S
通讯作者：
Avraham S
影响因子：
6.2
作者：
Chung, GG;Yoon, HH;Burtness, BA
通讯作者：
Burtness, BA
影响因子：
120.1
作者：
Ferrara, Napoleone;Adamis, Anthony P.
通讯作者：
Adamis, Anthony P.