Leukotriene B 4 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

Ji Min Seo, Sooyoung Park, Jae-Hong Kim

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57 Citations (Scopus)

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-3cells 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.

Original languageEnglish
Pages (from-to)13840-13849
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number17
DOIs
Publication statusPublished - 2012 Apr 20

Fingerprint

STAT3 Transcription Factor
Leukotriene B4
Matrix Metalloproteinase 2
Ovarian Neoplasms
Up-Regulation
Cells
Neoplasm Metastasis
Reactive Oxygen Species
Chemical activation
NADPH Oxidase
Small Interfering RNA
Nude Mice
Pharmacology
Phenotype
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

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title = "Leukotriene B 4 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-3cells 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.",
author = "Seo, {Ji Min} and Sooyoung Park and Jae-Hong Kim",
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AU - Kim, Jae-Hong

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AB - 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-3cells 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.

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