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首页> 外文期刊>Cellular Physiology and Biochemistry >Upregulation of P21-Activated Kinase 1 (PAK1)/CREB Axis in Squamous Non-Small Cell Lung Carcinoma
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Upregulation of P21-Activated Kinase 1 (PAK1)/CREB Axis in Squamous Non-Small Cell Lung Carcinoma

机译：鳞状非小细胞肺癌中P21活化激酶1（PAK1）/ CREB轴的上调

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Background/Aims p21-activated Ser/Thr kinase 1 (PAK1) is essential for the genesis and development of many cancers. The purpose of this study was to investigate the role of the PAK1–cyclic AMP response element-binding (CREB) axis in non-small cell lung cancer (NSCLC) tumorigenesis and its related mechanisms. Methods Western blot assay and immunohistochemical staining were employed to investigate the PAK1 and CREB expression in the tissue microarray of human squamous NSCLC. Co-immunoprecipitation and immunofluorescence confocal assays were performed to determine the link between PAK1 and CREB. NSCLC xenograft models were used to study oncogenic function of PAK1 in vivo. Results We observed that PAK1 and CREB expression levels were significantly elevated in human squamous NSCLC-tissue specimens, compared with those in adjacent normal bronchial or bronchiolar epithelial-tissue specimens, as well as their phosphorylated forms, based on western blotting. We showed in vitro that PAK1 knockdown by small-interfering RNA (siRNA) blocked CREB phosphorylation, whereas plasmid-based PAK1 overexpression resulted in CREB phosphorylation at Ser133, based on western blotting. In addition, PAK1 interacted with CREB in co-immunoprecipitation assays. Additionally, our in vitro findings detected by flow cytometry revealed that PAK1 silencing attenuated cell cycle progression, inducing apoptosis. Inhibition of PAK1 expression reduced tumor sizes and masses by modulating CREB expression and activation in xenograft models. Conclusion These results suggest a novel mechanism whereby the PAK1–CREB axis drives carcinogenesis of squamous-cell carcinomas, and have important implications in the development of targeted therapeutics for squamous-cell lung cancer.
机译：背景/目的p21激活的Ser / Thr激酶1（PAK1）对于许多癌症的发生和发展至关重要。这项研究的目的是调查PAK1 –环AMP反应元件结合（CREB）轴在非小细胞肺癌（NSCLC）肿瘤发生中的作用及其相关机制。方法采用蛋白质印迹法和免疫组化染色技术检测人鳞状细胞癌组织微阵列中PAK1和CREB的表达。进行了共免疫沉淀和免疫荧光共聚焦测定，以确定PAK1和CREB之间的联系。 NSCLC异种移植模型用于研究PAK1在体内的致癌功能。结果我们观察到，与相邻的正常支气管或支气管上皮组织标本及其磷酸化形式相比，人鳞状NSCLC组织标本中PAK1和CREB的表达水平显着升高，基于Western印迹法。根据体外印迹，我们在体外显示了小干扰RNA（siRNA）引起的PAK1敲低可阻断CREB的磷酸化，而基于质粒的PAK1的过表达导致Ser133处的CREB磷酸化。此外，PAK1在共同免疫沉淀试验中与CREB相互作用。此外，通过流式细胞仪检测到的体外研究结果表明，PAK1沉默可减弱细胞周期进程，诱导细胞凋亡。抑制PAK1表达可通过调节CREB表达和激活异种移植模型来减少肿瘤大小和肿块。结论这些结果表明，PAK1-CREB轴可驱动鳞状细胞癌的发生，并在鳞状细胞肺癌靶向治疗的发展中具有重要意义。

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