Overexpression of CRM1 A Characteristic Feature in a Transformed Phenotype of Lung Carcinogenesis and a Molecular Target for Lung Cancer Adjuvant Therapy
Overexpression of CRM1 A Characteristic Feature in a Transformed Phenotype of Lung Carcinogenesis and a Molecular Target for Lung Cancer Adjuvant Therapy
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DOI：
10.1097/jto.0000000000000485
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发表时间：
2015-05-01
影响因子：
20.4
通讯作者：
Keohavong, Phouthone
中科院分区：
文献类型：
--
作者：
Gao, Weimin;Lu, Chuanwen;Keohavong, Phouthone
我们以前的研究表明，染色体区域维持1（CRM 1），各种癌症相关的“货物”蛋白的核输出受体，在调节肺癌发生中起重要作用，以响应烟草致癌物，4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）。本研究的目的是全面评估CRM 1在肺癌发展中的意义，并使用体外和体内模型研究靶向CRM 1治疗肺癌的治疗潜力。我们发现CRM 1不仅在肺癌患者和NNK治疗小鼠的肺肿瘤组织中过表达，而且在NNK转化的BEAS-2B人支气管上皮细胞中也过表达。此外，通过质粒载体转染在BEAS-2B细胞中稳定过表达CRM 1导致恶性细胞转化。此外，通过短发夹siRNA转染降低A549细胞中CRM 1表达水平导致体外和裸鼠致瘤活性降低，表明靶向CRM 1用于肺癌治疗的潜力。事实上，我们表明，顺铂对A549细胞的细胞毒性作用与CRM 1下调短发夹siRNA显着增加，与A549细胞相比，顺铂的细胞毒性作用变得进一步增强，当药物与链霉素B，CRM 1抑制剂，在体外和体内模型组合使用。肿瘤靶基因在这些过程中发挥着重要作用。这些数据表明CRM 1在肺癌发生中起重要作用，并为肺癌辅助治疗提供了新的靶点。
Our previous study showed that chromosome region maintenance 1 (CRM1), a nuclear export receptor for various cancer-associated "cargo" proteins, was important in regulating lung carcinogenesis in response to a tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The objectives of this study are to comprehensively evaluate the significance of CRM1 in lung cancer development and investigate the therapeutic potential of targeting CRM1 for lung cancer treatment using both in vitro and in vivo models. We showed that CRM1 was overexpressed not only in lung tumor tissues from both lung cancer patients and mice treated with NNK but also in NNK-transformed BEAS-2B human bronchial epithelial cells. Furthermore, stable overexpression of CRM1 in BEAS-2B cells by plasmid vector transfection led to malignant cellular transformation. Moreover, a decreased CRM1 expression level in A549 cells by short hairpin siRNA transfection led to a decreased tumorigenic activity both in vitro and in nude mice, suggesting the potential to target CRM1 for lung cancer treatment. Indeed, we showed that the cytotoxic effects of cisplatin on A549 cells with CRM1 down-regulated by short hairpin siRNA were significantly increased, compared with A549 cells, and the cytotoxic effects of cisplatin became further enhanced when the drug was used in combination with leptomycin B, a CRM1 inhibitor, in both in vitro and in vivo models. Cancer target genes were significantly involved in these processes. These data suggest that CRM1 plays an important role in lung carcinogenesis and provides a novel target for lung cancer adjuvant therapy.