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Secretion of IL-6 and IL-8 from lysophosphatidic acid-stimulated oral squamous cell carcinoma promotes osteoclastogenesis and bone resorption

 Young Sun Hwang  ;  Sun Kyoung Lee  ;  Kwang-Kyun Park  ;  Won-Yoon Chung 
 ORAL ONCOLOGY, Vol.48(1) : 40-48, 2012 
Journal Title
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Animals ; Biological Assay ; Blotting, Western ; Bone Neoplasms/metabolism* ; Bone Resorption/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Humans ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Lysophospholipids/pharmacology ; Mice ; Mouth Neoplasms/metabolism* ; Osteoclasts/metabolism ; RANK Ligand/metabolism ; Reverse Transcriptase Polymerase Chain Reaction
Lysophosphatidic acid ; IL-6 ; IL-8 ; Osteoclastogenesis ; Oral squamous cell carcinoma ; RANKL
Lysophosphatidic acid (LPA) is a bioactive lipid with a growth factor-like activity on a large range of cell types. Several pieces of evidence raise the possibility that LPA may play an important role in bone metastasis. Bone is a frequent metastatic site for oral cancer. However, the role of LPA in the progression of oral cancer metastasis to the bone is poorly understood. Here, we provide evidence for the role of LPA in the progression of oral cancer bone metastases and its regulatory mechanism. LPA induced the secretion of IL-6 and IL-8 in oral squamous cell carcinoma (OSCC). LPA-stimulated secretion of IL-6 and IL-8 is partly dependent on the LPA and EGF receptor (EGFR) pathways. ERK1/2 and Akt-mediated NF-κB and AP-1 were responsible for the LPA-induced IL-6 and IL-8 secretion. Moreover, conditioned medium (CM) derived from the LPA-stimulated OSCC supported osteoclast formation in bone marrow-derived macrophages (BMMs). Neutralization against both human IL-6 and IL-8 suppressed osteoclast formation induced by CM derived from the LPA-stimulated OSCC. Direct treatment with recombinant IL-6 (rIL-6) and/or soluble IL-6 receptor (sIL-6R), or IL-8 (rIL-8) reproduced the effect of the CM derived from the LPA-stimulated OSCC on osteoclast formation. In addition, CM derived from the LPA-stimulated OSCC induced receptor activator of nuclear factor (NF)-κB ligand (RANKL) expression in human osteoblasts and direct treatment with rIL-6 and/or sIL-6R or rIL-8 mimicked the effect of the CM derived from the LPA-stimulated OSCC for RANKL expression. Taken together, LPA may be a potent inducer of osteolytic factor IL-6 and IL-8 in OSCC. LPA-induced IL-6 and IL-8 exerted propound effects on RANKL expression in osteoblast and thereby promoted osteoclast formation from osteoclast precursors.
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5. Research Institutes (연구소) > Oral Cancer Research Institute (구강종양연구소) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Park, Kwang Kyun(박광균)
Lee, Sun Kyoung(이선경) ORCID logo https://orcid.org/0000-0002-3707-8050
Chung, Won Yoon(정원윤) ORCID logo https://orcid.org/0000-0001-8428-9005
Hwang, Young Sun(황영선)
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