title: Leptin promotes human endometriotic cell migration and invasion by up-regulating MMP-2 through the JAK2/STAT3 signaling pathway.
abstract: Despite evidence that leptin may play a role in the pathogenesis of endometriosis, the specific function of leptin in the migration and invasion of endometriotic cells is not well characterized. In this study, we investigated the effect of leptin on the migration, invasion and matrix metalloproteinase (MMP) expression levels of human endometriotic cells. We found that leptin stimulated the migration and invasion of endometriotic cells (11Z, 12Z and 22B) in a dose-dependent manner. Leptin receptor (ObR) siRNA significantly inhibited the migration and invasion induced by leptin in 11Z and 12Z cells. Leptin-induced migration and invasion were significantly attenuated by pretreatment with SB-3CT, a specific gelatinase (MMP-2 and MMP-9) inhibitor. In addition, leptin-induced increases in the mRNA and protein expression and enzyme activity of MMP-2 in 11Z and 12Z cells. Selectively inhibiting MMP-2 using siRNA and an inhibitor (GM6003), impaired the ability of leptin to stimulate the migration and invasion of endometriotic cells, suggesting that MMP-2 plays an essential role in leptin-induced migration and invasion. Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) inhibitor (AG490) significantly inhibited the migration, invasion and MMP-2 expression induced by leptin in endometriotic cells. Furthermore, the Extracellular signal-Regulated Kinase inhibitor PD98059 neutralized the migration and invasion promoting effects of leptin. Taken together, these results suggest that leptin may contribute to the migration and invasion abilities of endometriotic cells via the up-regulation of MMP-2 through an ObR-dependent JAK2/STAT3 signaling pathway.
authors.affiliation: Department of Life & Nanopharmaceutical Science, Kyung Hee University, Seoul, South Korea Division of Molecular Biology, College of Pharmacy, Kyung Hee University, Seoul, South Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Ahn
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Catholic University of Daegu, Daegu, South Korea.
authors.forename: Youn Seok
authors.initials: YS
authors.lastname: Choi
authors.affiliation: Department of Life & Nanopharmaceutical Science, Kyung Hee University, Seoul, South Korea Division of Molecular Biology, College of Pharmacy, Kyung Hee University, Seoul, South Korea jchoi@khu.ac.kr.
authors.forename: Jung-Hye
authors.initials: JH
authors.lastname: Choi
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen; D004151:Dipeptides / Q000494:pharmacology; D004338:Drug Combinations; D004717:Endometrium / Q000166:cytology* / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D007797:Laminin; D020738:Leptin / Q000494:pharmacology* / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011509:Proteoglycans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D013450:Sulfones / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D004338:Drug Combinations; D005419:Flavonoids; D006573:Heterocyclic Compounds, 1-Ring; C515448:LEPR protein, human; D007797:Laminin; D020738:Leptin; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D047428:Protein Kinase Inhibitors; D011509:Proteoglycans; D034741:RNA, Small Interfering; D054411:Receptors, Leptin; C429533:SB 3CT compound; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013450:Sulfones; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C059485:matrigel; D003094:Collagen; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: JAK2/STAT3; endometriosis; invasion; leptin; leptin receptor; matrix metalloprotease; migration