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- Title
Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer Aggressiveness.
- Authors
Jeong, Bo Young; Cho, Kyung Hwa; Yoon, Se-Hee; Park, Chang Gyo; Park, Hwan-Woo; Lee, Hoi Young; Nasser, Mohd W.
- Abstract
Lysophosphatidic acid (LPA), a bioactive lipid produced extracellularly by autotaxin (ATX), has been known to induce various pathophysiological events, including cancer cell invasion and metastasis. Discoidin domain receptor 2 (DDR2) expression is upregulated in ovarian cancer tissues, and is closely associated with poor clinical outcomes in ovarian cancer patients. In the present study, we determined a critical role and signaling cascade for the expression of DDR2 in LPA-induced ovarian cancer cell invasion. We also found ectopic expression of ATX or stimulation of ovarian cancer cells with LPA-induced DDR2 expression. However, the silencing of DDR2 expression significantly inhibited ATX- and LPA-induced ovarian cancer cell invasion. In addition, treatment of the cells with pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and mTOR abrogated LPA-induced DDR2 expression. Moreover, we observed that HIF-1α, located downstream of the mTOR, is implicated in LPA-induced DDR2 expression and ovarian cancer cell invasion. Finally, we provide evidence that LPA-induced HIF-1α expression mediates Twist1 expression to upregulate DDR2 expression. Collectively, the present study demonstrates that ATX, and thereby LPA, induces DDR2 expression through the activation of the PI3K/Akt/mTOR/HIF-1α/Twist1 signaling axes, aggravating ovarian cancer cell invasion.
- Subjects
OVARIAN cancer; PHOSPHATIDYLINOSITOL 3-kinases; LYSOPHOSPHOLIPIDS; INDUCED ovulation; TREATMENT effectiveness; DISCOIDIN domain receptor 2
- Publication
International Journal of Molecular Sciences, 2021, Vol 22, Issue 10, p5374
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms22105374