p21-activated kinase 3 is overexpressed in thymic neuroendocrine tumors (carcinoids) with ectopic ACTH syndrome and participates in cell migration.
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 NH(2)-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.
Liu
Rui-xin
RX
Shanghai Key Laboratory for Endocrine Tumors, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
Wang
Wei-qing
WQ
Ye
Lei
L
Bi
Yu-fang
YF
Fang
Hai
H
Cui
Bin
B
Zhou
Wei-wei
WW
Dai
Meng
M
Zhang
Ji
J
Li
Xiao-ying
XY
Ning
Guang
G
D000182:ACTH Syndrome, Ectopic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002276:Carcinoid Tumor / Q000235:genetics* / Q000473:pathology; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009479:Neuropeptides / Q000235:genetics; D013953:Thymus Neoplasms / Q000235:genetics* / Q000473:pathology; D054462:p21-Activated Kinases / Q000235:genetics*; D020744:rac GTP-Binding Proteins / Q000235:genetics; D020830:rac1 GTP-Binding Protein
D009479:Neuropeptides; C484602:Rac1 protein, mouse; D000324:Adrenocorticotropic Hormone; C515911:PAK3 protein, human; C515912:Pak3 protein, mouse; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein