title: Homeobox gene HLX is a regulator of HGF/c-met-mediated migration of human trophoblast-derived cell lines.
abstract: Homeobox gene transcription factors play a critical role in normal placental development and are expressed in specialized trophoblast cells. Abnormal trophoblast function is associated with clinically significant pregnancy disorders, including fetal growth restriction (FGR). Our previous studies demonstrated that homeobox gene HLX is expressed in proliferating and migrating (but not invading) human trophoblast cells and that HLX expression is significantly decreased in human FGR. We have also shown that HLX is a regulator of colony-stimulating-factor-1-dependent trophoblast proliferation. Hepatocyte growth factor (HGF) activates trophoblast cell migration in a paracrine fashion, and its receptor, c-met, is expressed on trophoblast cells. Given that HGF is a regulator of trophoblast migration, we hypothesize that HLX is a mediator of HGF/c-met-dependent trophoblast migration but not invasion. Here we investigated the potential role of HLX in HGF/c-met-mediated trophoblast migration and invasion in two human trophoblast-derived cell lines, SGHPL-4 and HTR-8/SVneo. Results showed that in cultured trophoblast cells, HGF stimulation significantly increased HLX mRNA and protein expression. HLX inactivation significantly decreased trophoblast migration but not invasion. When HLX was inactivated in the presence of HGF stimulation, migration remained significantly decreased. SU11274-mediated inhibition of the receptor c-met significantly decreased HLX mRNA and protein expression. In the presence of HGF stimulation, HLX expression remained significantly decreased with c-met inhibition. This is the first study to show that homeobox gene HLX is a downstream effector gene of HGF, that HLX regulates human trophoblast-derived cell migration, and that HGF, via receptor c-met, acts through HLX to control cell migration.
authors.affiliation: Department of Obstetrics and Gynaecology, University of Melbourne, The Royal Women's Hospital, Parkville, Victoria, Australia. gayaram@gmail.com
authors.forename: Gayathri
authors.initials: G
authors.lastname: Rajaraman
authors.forename: Padma
authors.initials: P
authors.lastname: Murthi
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Brennecke
authors.forename: Bill
authors.initials: B
authors.lastname: Kalionis
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D003094:Collagen / Q000502:physiology; D004338:Drug Combinations; D005260:Female; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007797:Laminin / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D010920:Placenta / Q000166:cytology / Q000502:physiology*; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011509:Proteoglycans / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000502:physiology*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics*; D014327:Trophoblasts
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D004338:Drug Combinations; C084058:HLX protein, human; D018398:Homeodomain Proteins; D007211:Indoles; D007797:Laminin; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011509:Proteoglycans; D034741:RNA, Small Interfering; D013449:Sulfonamides; D014157:Transcription Factors; C059485:matrigel; D012313:RNA; D017228:Hepatocyte Growth Factor; D003094:Collagen; D019859:Proto-Oncogene Proteins c-met