Nestin regulates proliferation, migration, invasion and stemness of lung adenocarcinoma
Nestin regulates proliferation, migration, invasion and stemness of lung adenocarcinoma
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DOI：
10.3892/ijo.2014.2278
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发表时间：
2014-04-01
影响因子：
5.2
通讯作者：
Ishiwata, Toshiyuki
中科院分区：
文献类型：
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作者：
Narita, Kosuke;Matsuda, Yoko;Ishiwata, Toshiyuki
肺癌是世界上最常见的癌症，也是癌症相关死亡的最常见原因。巢蛋白是一种VI类中间丝，已知是癌症干细胞（CSC）标志物以及神经上皮干细胞标志物。巢蛋白的高表达水平在几种类型的癌症中有报道，包括肺癌、胰腺癌和前列腺癌。巢蛋白被认为调节肿瘤细胞的增殖、迁移、侵袭和CSC特性。在此，我们证实了nestin在非小细胞肺癌（NSCLC）中的表达：免疫组化分析在48例腺癌（AD）中的20例（41.7%）和47例鳞癌中的25例（53.2%）的细胞质中检测到nestin蛋白表达。Nestin免疫反应性不仅与NSCLC的肿瘤大小和淋巴结转移显著相关，而且与AD手术患者的不良生存率显著相关。巢蛋白在包括H1975和PC-3在内的几种肺AD细胞系中的高和中等表达水平得到证实。巢蛋白抑制shRNA可降低AD细胞的增殖、迁移、侵袭和球体形成。相应地，巢蛋白基因转染上调巢蛋白导致相反的变化。此外，Akt抑制剂IV通过SRY-box containing protein 2（Sox 2）下调有效地降低巢蛋白表达，并克服巢蛋白上调诱导的增强的球体形成。总之，我们的研究结果表明，巢蛋白与AD的攻击性和干性相关。因此，通过Akt/Sox 2调节巢蛋白是根除肺AD中CSC的新治疗方法的有希望的候选者。
Lung cancer is the most common cancer and the most common cause of cancer-related death in the world. Nestin, a class VI intermediate filament, is known to be a cancer stem cell (CSC) marker as well as a neuroepithelial stem cell marker. High expression levels of nestin are reported in several types of cancers including lung, pancreatic and prostate cancers. Nestin is thought to regulate tumor cell proliferation, migration, invasion and CSC properties. Here, we confirmed nestin expression in non-small cell lung cancer (NSCLC): Immunohistochemical analysis in surgical specimens detected nestin protein expression in the cytoplasm of 20 of 48 adenocarcinoma (AD) cases (41.7%) and 25 of 47 squamous cell carcinoma cases (53.2%). Nestin immunore-activity significantly correlated with not only tumor size and lymph node metastasis in NSCLC, but also poor survival in surgical patients with AD. High and moderate expression levels of nestin were confirmed in several lung AD cell lines including H1975 and PC-3. Nestin inhibition by shRNA decreased proliferation, migration, invasion and sphere formation in AD cells. Correspondingly, nestin upregulation by nestin gene transfection resulted in the opposite changes. Moreover, Akt inhibitor IV effectively decreased nestin expression via SRY-box containing protein 2 (Sox2) down-regulation and overcame the enhanced sphere formation induced by nestin upregulation. Overall, our results show that nestin correlates with the aggressiveness and stemness of AD. Regulation of nestin via Akt/Sox2 is, thus, a promising candidate for novel therapeutic approaches to eradicate CSCs in lung AD.