Immunoglobulin-like transcript 4 promotes tumor progression and metastasis and up-regulates VEGF-C expression via ERK signaling pathway in non-small cell lung cancer
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Pei Zhang1,2*, Xiaosun Guo3*, Juan Li2, Shuwen Yu4, Linlin Wang2, Guosheng Jiang5, Dong Yang2, Zhaolong Wei6, Nan Zhang2, Jie Liu2, Yuping Sun2
1Department of Oncology, School of Medicine, Shandong University, Jinan, Shandong, P. R. China
2Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong, P. R. China
3Department of Pathophysiology, School of Medicine, Shandong University, Jinan, Shandong, P. R. China
4Department of Pharmacy, Jinan Central Hospital, Shandong University, Jinan, Shandong, P. R. China
5Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, P. R. China
6Department of Medical Imaging, Jinan Central Hospital, Shandong University, Jinan, Shandong, P. R. China
*These authors have contributed equally to this work
Yuping Sun, e-mail: email@example.com
Keywords: ILT4, tumor progression, ERK1/2, VEGF-C, NSCLC
Received: November 09, 2014 Accepted: March 16, 2015 Published: April 13, 2015
Immunoglobulin-like transcript (ILT) 4 has long been thought to be cell-surface molecule in certain immune cells and negatively regulates immune response. Recently, overexpression of ILT4 has been observed in a few cancers with unknown function. Here, we showed manipulation of ILT4 affected non-small cell lung cancer (NSCLC) cell proliferation, migration and invasion in vitro analyses. In vivo, ILT4 promoted the tumor growth and metastasis. Furthermore, the phosphorylation of extracellular regulated protein kinases (ERK1/2) was enhanced in ILT4 overexpressing NSCLC cells. ERK1/2 specific inhibitor U0126 suppressed the proliferation, migration and invasion of those cells. Stepwise investigations demonstrated that vascular endothelial growth factor C (VEGF-C) was the downstream effector of ILT4 and ERK1/2. Silence of VEGF-C attenuated the migration and invasion activity of ILT4 overexpressing cells. Moreover, Kaplan-Meier survival analysis indicated that NSCLC patients with ILT4 positive expression had a poor patient survival. ILT4 and VEGF-C expression had notable positive correlation in cancer cells, and their co-expression was significantly associated with adverse prognostic factors. Our findings suggest that ILT4 drives NSCLC development in part on activation of ERK signaling which in turn upregulates VEGF-C. ILT4 could be a novel cancer therapeutic target for NSCLC.
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