Lysophosphatidic acid receptor 2/3-mediated IL-8-dependent angiogenesis in cervical cancer cells
Journal
International Journal of Cancer
Journal Volume
131
Journal Issue
4
Pages
789-802
Date Issued
2012
Author(s)
Abstract
The expression of lysophosphatidic acid (LPA)-specific receptors in cervical cancer has not been clearly defined. In this study, we identified LPA1, LPA2 and LPA3 receptors' mRNA in SiHa, HeLa and CaSki cell lines by RT-PCR. These receptors were not associated with tumor cell proliferation in vitro. We then used a xenograph animal model to evaluate the effects of these receptors on in vivo cervical cancer tumorigenicity. When SiHa cells with different receptor expression patterns were seeded on the backs of SCID mice, the resulting knockout of both LPA2 and LPA3 significantly attenuated tumor growth; this decrease in tumor growth was found to be linked with decreased angiogenesis (microvessel density), suggesting that LPA2 and LPA3 are crucial for in vivo tumor growth through an angiogenic mechanism. We further investigated this mechanism of LPA receptor 2/3-mediated angiogenic capability by analyzing angiogenic factors in protein lysates from receptor knockout tumors, by detecting interleukin (IL-8) mRNA expression after treating with siRNA, by evaluating the biological role of LPA-enhanced IL-8 via endothelial cell tube formation, monolayer permeability, migration and cell growth assays, and by IL-8 knockout xenograft mice modeling. We found that the angiogenesis is mediated through IL-8. Finally, we evaluated the regulation pathways involved in LPA-induced IL-8 expression. We found that LPA receptor 2/3-mediated IL-8 expression occurs through Gi/PI3K/AKT, Gi/PKC and IηB/NF-ηB signaling. In conclusion, we propose that LPA2 and LPA3 might play an important role in cervical cancer tumor growth through IL-8-dependent angiogenesis. Copyright ? 2011 UICC.
SDGs
Other Subjects
2 (2 amino 3 methoxyphenyl)chromone; 2 [1 (3 amidinothiopropyl) 1h indol 3 yl] 3 (1 methyl 1h indol 3 yl)maleimide; 2 morpholino 8 phenylchromone; 4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole; anthra[1,9 cd]pyrazol 6(2h) one; I kappa B; immunoglobulin enhancer binding protein; interleukin 8; lysophosphatidic acid receptor; lysophosphatidic acid receptor 1; lysophosphatidic acid receptor 2; lysophosphatidic acid receptor 3; messenger RNA; phosphatidylinositol 3 kinase; protein hydrolysate; protein kinase B; protein kinase C; small interfering RNA; unclassified drug; angiogenesis; animal experiment; animal model; article; cancer cell; cancer inhibition; carcinogenicity; cell growth; cell membrane permeability; cell migration; cell proliferation; controlled study; drug efficacy; endothelium cell; enzyme regulation; female; human; human cell; in vitro study; in vivo study; mouse; nonhuman; priority journal; protein analysis; protein expression; reverse transcription polymerase chain reaction; signal transduction; treatment response; tumor growth; uterine cervix cancer; xeroradiography; Base Sequence; Blotting, Western; Cell Line, Tumor; Culture Media, Conditioned; DNA Primers; Female; Humans; Immunoenzyme Techniques; Interleukin-8; Neovascularization, Pathologic; NF-kappa B; Phosphatidylinositol 3-Kinases; Protein Kinase C; Real-Time Polymerase Chain Reaction; Receptors, Lysophosphatidic Acid; RNA, Small Interfering; Signal Transduction; Uterine Cervical Neoplasms
Type
journal article