title: Leukotriene B4 receptor-2 promotes invasiveness and metastasis of ovarian cancer cells through signal transducer and activator of transcription 3 (STAT3)-dependent up-regulation of matrix metalloproteinase 2.
abstract: Ovarian cancer is the most lethal gynecologic malignancy in women. Despite the fact that the metastatic spread is associated with the majority of deaths from ovarian cancer, the molecular mechanisms regulating the invasive and metastatic phenotypes of ovarian cancer are poorly understood. In this study, we demonstrated that BLT2, a low affinity leukotriene B(4) receptor, is highly expressed in OVCAR-3 and SKOV-3 human ovarian cancer cells, and that this receptor plays a key role in the invasiveness and metastasis of these cells through activation of STAT3 and consequent up-regulation of matrix metalloproteinase 2 (MMP2). In addition, our results suggest that activation of NAD(P)H oxidase-4 (NOX4) and subsequent reactive oxygen species (ROS) generation lie downstream of BLT2, mediating the stimulation of STAT3-MMP2 cascade in this process. For example, knockdown of BLT2 or NOX4 using each specific siRNA suppressed STAT3 stimulation and MMP2 expression. Similarly, inhibition of STAT3 suppressed the expression of MMP2, thus leading to attenuated invasiveness of these ovarian cancer cells. Finally, the metastasis of SKOV-3 cells in nude mice was markedly suppressed by pharmacological inhibition of BLT2. Together, our results implicate a BLT2-NOX4-ROS-STAT3-MMP2 cascade in the invasiveness and metastasis of ovarian cancer cells.
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Seo
authors.forename: Sooyoung
authors.initials: S
authors.lastname: Park
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000494:pharmacology; D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D017382:Reactive Oxygen Species; D018102:Receptors, Leukotriene B4 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C485878:LTB4R2 protein, human; D017382:Reactive Oxygen Species; D018102:Receptors, Leukotriene B4; D050796:STAT3 Transcription Factor; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D020778:Matrix Metalloproteinase 2