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

2015

Oncotarget

Self Cite

Inflammation and local inflammatory mediators are inextricably linked to tumor progression through complex pathways in the tumor microenvironment. Lipopolysaccharide (LPS) exposure to tumor cells has been suggested to promote tumor invasiveness and metastasis. However, the detailed signaling mechanism involved has not been elucidated. In this study, we showed that LPS upregulated the expression of leukotriene B4 receptor-2 (BLT2) and the synthesis of BLT2 ligands in MDA-MB-231 and MDA-MB-435 breast cancer cells, thereby promoting invasiveness. BLT2 depletion with siRNA clearly attenuated LPS-induced invasiveness. In addition, we demonstrated that myeloid differentiation primary response gene 88 (MyD88) lies upstream of BLT2 in LPS-potentiated invasiveness and that this ‘MyD88-BLT2’ cascade mediates activation of NF-κB and the synthesis of IL-6 and IL-8, which are critical for the invasiveness and aggression of breast cancer cells. LPS-driven metastasis of MDA-MB-231 cells was also markedly suppressed by the inhibition of BLT2. Together, our results demonstrate, for the first time, that LPS potentiates the invasiveness and metastasis of breast cancer cells via a ‘MyD88-BLT2’-linked signaling cascade.

Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Myeloid differentiation primary response gene 88-leukotriene B4 receptor 2 cascade mediates lipopolysaccharide-potentiated invasiveness of breast cancer cells

Park

2015

Oncotarget

Self Cite

“…The levels of leukotriene B 4 (LTB 4 ), one of the local lipid mediators in the inflammatory microenvironment, and its receptor, BLT2, are markedly up-regulated by oncogenic Ras and mediate Ras-associated tumorigenic activities (10 -12). Expression of BLT2 in ovarian and breast cancer tissue is increased in advanced stages and is associated with poor clinical outcome (13)(14)(15). Furthermore, autocrine or paracrine BLT2 signaling mediates the invasiveness and metastasis of ovarian, bladder, and breast cancer cells (14,16,17).…”

mentioning

confidence: 99%

Ras Promotes Transforming Growth Factor-β (TGF-β)-induced Epithelial-Mesenchymal Transition via a Leukotriene B4 Receptor-2-linked Cascade in Mammary Epithelial Cells

Choi

Journal of Biological Chemistry

2014

Self Cite

Background:The mechanism by which oncogenic Ras contributes to epithelial-mesenchymal transition (EMT) is not clearly defined. Results:The "BLT2-ROS-NF-B"-linked cascade lies downstream of Ras and promotes EMT. Conclusion: Activation of leukotriene B 4 receptor-2 (BLT2)-linked pathway contributes to EMT in mammary epithelial cells. Significance: These findings suggest that BLT2 is a novel regulator of EMT in mammary epithelial cells.

“…These results are in line with previous studies in other cell models demonstrating that STAT3 seems to be involved in the LIF-induced MMP release; for example, in fibroblasts it activates MMP-9 release (Wang et al 2007). In ovarian cancer cells, inhibition of STAT3 led to a decrease in MMP-2 activity in cell culture supernatant (Seo et al 2012). Additional LIF could not reverse the effects of STAT3 inhibition on MMP-2 and MMP-9 expression.…”

Section: Discussionmentioning

confidence: 87%

Oncostatin M and leukaemia inhibitory factor trigger signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 pathways but result in heterogeneous cellular responses in trophoblast cells

Chaiwangyen

Ospina‐Prieto

Morales-Prieto

et al. 2016

Reprod. Fertil. Dev.

Leukaemia inhibitory factor (LIF) and oncostatin M (OSM) are pleiotropic cytokines present at the implantation site that are important for the normal development of human pregnancy. These cytokines share the cell membrane receptor subunit gp130, resulting in similar functions. The aim of this study was to compare the response to LIF and OSM in several trophoblast models with particular regard to intracellular mechanisms and invasion. Four trophoblast cell lines with different characteristics were used: HTR-8/SVneo, JEG-3, ACH-3P and AC1-M59 cells. Cells were incubated with LIF, OSM (both at 10ngmL(-1)) and the signal transducer and activator of transcription (STAT) 3 inhibitor S3I-201 (200µM). Expression and phosphorylation of STAT3 (tyr(705)) and extracellular regulated kinase (ERK) 1/2 (thr(202/204)) and the STAT3 DNA-binding capacity were analysed by Western blotting and DNA-binding assays, respectively. Cell viability and invasiveness were assessed by the methylthiazole tetrazolium salt (MTS) and Matrigel assays. Enzymatic activity of matrix metalloproteinase (MMP)-2 and MMP-9 was investigated by zymography. OSM and LIF triggered phosphorylation of STAT3 and ERK1/2, followed by a significant increase in STAT3 DNA-binding activity in all tested cell lines. Stimulation with LIF but not OSM significantly enhanced invasion of ACH-3P and JEG-3 cells, but not HTR-8/SVneo or AC1-M59 cells. Similarly, STAT3 inhibition significantly decreased the invasiveness of only ACH-3P and JEG-3 cells concomitant with decreases in secreted MMP-2 and MMP-9. OSM shares with LIF the capacity to activate ERK1/2 and STAT3 pathways in all cell lines tested, but their resulting effects are dependent on cell type. This suggests that LIF and OSM may partially substitute for each other in case of deficiencies or therapeutic interventions.