TAZ mediates lysophosphatidic acid-induced migration and proliferation of epithelial ovarian cancer cells.
BACKGROUND
Transcriptional co-activator with PDZ-binding motif (TAZ), a downstream effector of the Hippo pathway, has been reported to regulate organ size, tissue homeostasis, and tumorigenesis by acting as a transcriptional co-activator. Lysophosphatidic acid (LPA) is a bioactive lipid implicated in tumorigenesis and metastasis of ovarian cancer through activation of G protein-coupled receptors. However, the involvement of TAZ in LPA-induced tumorigenesis of ovarian cancer has not been elucidated.


METHODS
In order to demonstrate the role of TAZ in LPA-stimulated tumorigenesis, the effects of LPA on TAZ expression and cell migration were determined by Western blotting and chemotaxis analyses in R182 human epithelial ovarian cancer cells.


CONCLUSIONS
Treatment of R182 cells with the LPA receptor inhibitor Ki16425 blocked LPA-induced cell migration. In addition, transfection of R182 cells with small interfering RNA specific for LPA receptor 1 resulted in abrogation of LPA-stimulated cell migration. LPA induced phosphorylation of ERK and p38 MAP kinase in R182 cells and pretreatment of cells with the MEK-ERK pathway inhibitor U0126, but not the p38 MAPK inhibitor SB202190, resulted in abrogation of LPA-induced cell migration. Pretreatment of R182 cells with U0126 attenuated LPA-induced mRNA levels of TAZ and its transcriptional target genes, such as CTGF and CYR61, without affecting phosphorylation level of YAP. These results suggest that MEK-ERK pathway plays a key role in LPA-induced cell migration and mRNA expression of TAZ in R182 cells, without affecting stability of TAZ protein. In addition, small interfering RNA-mediated silencing of TAZ expression attenuated LPA-stimulated migration of R182 cells. These results suggest that TAZ plays a key role in LPA-stimulated migration of epithelial ovarian cancer cells.
Medical Research Center for Ischemic Tissue Regeneration, School of Medicine, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea.
Geun Ok
GO
Jeong
Sang Hun
SH
Shin
Eun Jin
EJ
Seo
Yang Woo
YW
Kwon
Soon Chul
SC
Heo
Ki-Hyung
KH
Kim
Man-Soo
MS
Yoon
Dong-Soo
DS
Suh
Jae Ho
JH
Kim
D002070:Butadienes / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000633:toxicity*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy; D009570:Nitriles / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011422:Propionates / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D002070:Butadienes; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D007555:Isoxazoles; D008246:Lysophospholipids; D009570:Nitriles; D011422:Propionates; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C113580:U 0126; C551991:WWTR1 protein, human; C032881:lysophosphatidic acid