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p21-Activated kinase 3 is overexpressed in thymic neuroendocrine tumors (carcinoids) with ectopic ACTH syndrome and participates in cell migration

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Abstract

Thymic carcinoid is an important component of the tumor spectrum causing Ectopic ACTH Syndrome (EAS) and usually carries a poor prognosis. Efforts have been focused on exploring the mechanism of the excessive ACTH production in non-pituitary tumors, whereas few studies have reported the molecular events underlying the tumor progression. In this study, seven patients with ACTH producing thymic carcinoids were enrolled. Of note is that five of them showed either lymph node metastasis, local invasion or distant metastasis. By using cDNA profiling approach, we evaluated the expression of cell adhesion pathway genes and found a remarkable overexpression of p21-activated kinase 3 (PAK3) in all thymic carcinoids which was further confirmed at both transcriptional and translational level. RAC1, an upstream activator of PAK3, was also overexpressed in thymic carcinoids. Overexpression of PAK3 in NIH3T3 cell enhanced cell migration and invasion. Importantly, we observed c-Jun NH2-terminal kinase (JNK) was activated in PAK3 transfected cells, and inhibition of JNK activity by SP600125, a JNK pathway inhibitor, abolished PAK3 mediated cell migration. Activation of JNK pathway was also detected in thymic carcinoid with high level of PAK3 expression. Our findings suggested a potential role of PAK3 in the progression of ACTH-producing thymic carcinoid.

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Acknowledgments

We greatly appreciate the patients for their cooperation in this study. This work was supported by the grants from the National Natural Science Foundation of China (No. 30725037, 30771018 and 30871203). The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

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Authors and Affiliations

  1. Shanghai Key Laboratory for Endocrine Tumors, Department of Endocrinology and Metabolism, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases and Shanghai E-institute for Endocrinology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People’s Republic of China

    Rui-xin Liu, Wei-qing Wang, Lei Ye, Yu-fang Bi, Bin Cui, Wei-wei Zhou, Meng Dai, Xiao-ying Li & Guang Ning

  2. Laboratory for Endocrine & Metabolic Diseases of Institute of Health Science, Shanghai JiaoTong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 227 South ChongQing Road, Shanghai, 200025, People’s Republic of China

    Bin Cui, Xiao-ying Li & Guang Ning

  3. State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People’s Republic of China

    Hai Fang & Ji Zhang

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  1. Rui-xin Liu
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  2. Wei-qing Wang
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Correspondence to Guang Ning.

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Rui-xin Liu and Wei-qing Wang contributed equally to this paper.

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Liu, Rx., Wang, Wq., Ye, L. et al. p21-Activated kinase 3 is overexpressed in thymic neuroendocrine tumors (carcinoids) with ectopic ACTH syndrome and participates in cell migration. Endocr 38, 38–47 (2010). https://doi.org/10.1007/s12020-010-9324-6

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