Carcinogenesis Advance Access originally published online on January 23, 2009
Carcinogenesis 2009 30(4):566-574; doi:10.1093/carcin/bgp023
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Leptin enhances cell migration in human chondrosarcoma cells through OBRl leptin receptor
1 Graduate Institute of Sports and Health, National Changhua University of Education, Changhua County 500, Taiwan
2 Department of Pharmacology, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404, Taiwan
3 Department of Orthopaedics, China Medical University Hospital, Taichung 404, Taiwan
4 Department of Materials Science and Engineering, Feng Chia University, Taichung 407, Taiwan
5 Department of Neurosurgery, Taichung Veterans General Hospital, Taichung 407, Taiwan
6 Center for General Education, Jen-Teh Junior College of Medicine, Miaoli County 356, Taiwan
7 Department of Orthopaedic, China Medical University Beigang Hospital, Yun-Lin County 651, Taiwan
8 School of Chinese Medicine
9 Graduate Institute of Chinese Medical Science
10 Graduate Institute of Basic Medical Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404, Taiwan
* To whom correspondence should be addressed. Department of Pharmacology, College of Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan. Tel: +886 4 22053366 ext. 2228; Fax: +886 4 22053764; Email: chtang{at}mail.cmu.edu.tw
Correspondence may also be addressed to Wen-Pei Tseng; Tel: +886 4 7232105; Fax: +886 4 22053764; Email: twp{at}cc.ncue.edu.tw
Leptin, an adipocyte-derived cytokine that is closely associated with obesity, has recently been shown to be involved in carcinogenesis and cancer progression. Integrins are the major adhesive molecules in mammalian cells and have been associated with metastasis of cancer cells. In this study, we found that leptin increased the migration and the expression of 
vβ3 integrin in human chondrosarcoma cells. We also found that human chondrosarcoma tissues and chondrosarcoma cell lines had significant expression of the long form (OBRl) leptin receptor, which was higher than that in normal cartilage and human primary chondrocyte. Leptin-mediated migration and integrin upregulation were attenuated by OBRl receptor antisense oligonucleotide. Activations of insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), Akt and nuclear factor-
B (NF-B) pathways after leptin treatment were demonstrated, and leptin-induced expression of integrin and migration activity was inhibited by the specific inhibitor, small-interfering RNA and mutant of IRS-1, PI3K, Akt and NF-B cascades. Taken together, our results indicated that leptin enhances the migration of chondrosarcoma cells by increasing vβ3 integrin expression through the OBR1/IRS-1/PI3K/Akt/NF-B signal transduction pathway.
Abbreviations: FBS, fetal bovine serum; IKK, IB kinase; IRS, insulin receptor substrate; JAK2, janus kinase 2; mRNA, messenger RNA; NF-B, nuclear factor-B; ODN, Oligonucleotide; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PDTC, pyrrolidine dithiocarbamate; PI3K, phosphatidylinositol 3-kinase; qPCR, quantitative real-time PCR; siRNA, small-interfering RNA; STAT, signal transducers and activators of transcription; TPCK, N-tosylphenylalanyl-chloromethyl-ketone
These authors contributed equally to this work. Received September 5, 2008; revised January 7, 2009; accepted January 11, 2009.