Leptin induces migration and invasion of glioma cells through MMP-13 production.
Leptin, the product of the obese gene, plays an important role in the regulation of body weight by coordinating metabolism, feeding behavior, energy balance, and neuroendocrine responses. However, regulation of leptin gene expression in the central nervous system is different from that in the adipocytes. In addition, leptin has been found in many tumor cell lines and has been shown to have mitogenic and angiogenic activity in a number of cell types. Glioma is the most common primary adult brain tumor with poor prognosis because of the spreading of tumor cell to the other regions of brain easily. Here we found that malignant C6 glioma cells expressed more leptin and leptin receptors than nonmalignant astrocytes. Furthermore, it was found that exogenous application of leptin enhanced the migration and invasion of C6 glioma cells. In addition, we found that the expression of matrix metalloproteinase-13 (MMP-13) but not of MMP-2 and MMP-9 was increased in response to leptin stimulation. The leptin-induced increase of cell migration and invasion was antagonized by MMP-13 neutralizing antibody or silencing MMP-13. The up-regulation of MMP-13 induced by leptin was mainly through p38 MAP kinase and NF-kappaB pathway. In addition, migration-prone sublines demonstrate that cells with increasing migration ability had more expression of MMP-13 and leptin. Taken together, these results indicate that leptin enhanced migration and invasion of C6 glioma cells through the increase of MMP-13 production.
Yeh
Wei-Lan
WL
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Lu
Dah-Yuu
DY
Lee
Ming-Jen
MJ
Fu
Wen-Mei
WM
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020738:Leptin / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D000906:Antibodies; D004791:Enzyme Inhibitors; D020738:Leptin; D053509:Matrix Metalloproteinase 13; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D054411:Receptors, Leptin; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase