Insulin-like growth factor-independent insulin-like growth factor binding protein 3 promotes cell migration and lymph node metastasis of oral squamous cell carcinoma cells by requirement of integrin β1
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Yi-Chen Yen1,*, Jenn-Ren Hsiao2,*, Shih Sheng Jiang1, Jeffrey S. Chang3, Ssu-Han Wang1, Ying-Ying Shen4, Chung-Hsing Chen5, I-Shou Chang1,5, Jang-Yang Chang6, Ya-Wen Chen1,7
1National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
2Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
3National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
4Pathology Core Laboratory, National Health Research Institutes, Miaoli, Taiwan
5Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
6Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan
7Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
*These authors have contributed equally to this work
Ya-Wen Chen, e-mail: [email protected]
Keywords: oral squamous cell carcinoma, lymph node metastasis, migration, insulin-like growth factor binding protein 3, integrin β1
Received: August 11, 2015 Accepted: October 05, 2015 Published: October 19, 2015
Frequent metastasis to the cervical lymph nodes leads to poor survival of patients with oral squamous cell carcinoma (OSCC). To understand the underlying mechanisms of lymph node metastasis, two sublines were successfully isolated from cervical lymph nodes of nude mice through in vivo selection, and identified as originating from poorly metastatic parental cells. These two sublines specifically metastasized to cervical lymph nodes in 83% of mice, whereas OEC-M1 cells did not metastasize after injection into the oral cavity. After gene expression analysis, we identified insulin-like growth factor binding protein 3 (IGFBP3) as one of the significantly up-regulated genes in the sublines in comparison with their parental cells. Consistently, meta-analysis of the public microarray datasets and IGFBP3 immunohistochemical analysis revealed increased both levels of IGFBP3 mRNA and protein in human OSCC tissues when compared to normal oral or adjacent nontumorous tissues. Interestingly, the up-regulated IGFBP3 mRNA expression was significantly associated with OSCC patients with lymph node metastasis. IGFBP3 knockdown in the sublines impaired and ectopic IGFBP3 expression in the parental cells promoted migration, transendothelial migration and lymph node metastasis of orthotopic transplantation. Additionally, ectopic expression of IGFBP3 with an IGF-binding defect sustained the IGFBP3-enhanced biological functions. Results indicated that IGFBP3 regulates metastasis-related functions of OSCC cells through an IGF-independent mechanism. Furthermore, exogenous IGFBP3 was sufficient to induce cell motility and extracellular signal-regulated kinase (ERK) activation. The silencing of integrin β1 was able to impair exogenous IGFBP3-mediated migration and ERK phosphorylation, suggesting a critical role of integrin β1 in IGFBP3-enchanced functions.
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