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.
Highlights
Ovarian cancer is a deadly disease, being the fifth leading cause of cancer-associated death among women [1]
Given that more than 40 times more Lysophosphatidic acid (LPA) is observed in both the plasma and the ascites of ovarian cancer patients [10], and that Discoidin domain receptor 2 (DDR2) is associated with poor clinical outcomes in ovarian cancer patients [20,21], we explore the role of DDR2 in LPA-induced ovarian cancer cell invasion
Since ovarian cancer 2780 and ES2 cells express the DDR2 protein associated with ovarian cancer metastasis [21], we first stimulated these cells with LPA and observed markedly upregulated DDR2 expression in a dose-dependent manner (Figure 1a)
Summary
Ovarian cancer is a deadly disease, being the fifth leading cause of cancer-associated death among women [1]. LPA promotes ovarian cancer invasion through a Ras/Rho/ROCK signaling pathway and through proteolytic enzyme secretion [11] This biolipid induces HIF-1α expression to increase VEGF expression and ovarian cancer progression [12]. Located on chromosome 1q23.3, discoidin domain receptor 2 (DDR2) is a member of the receptor tyrosine kinase (RTK) family [14,15,16], and has been closely associated with the progression of various cancers, including breast and prostate cancer [17,18,19] This collagen receptor DDR2 expression is upregulated in ovarian cancer tissues, and is associated with poor clinical outcomes in ovarian cancer patients [20,21,22]. We in the present study determined the role of DDR2 in LPA-induced ovarian cancer cell invasion, and found that LPA upregulates DDR2 expression through the HIF-1α/Twist signaling cascade to promote ovarian cancer cell invasion, expanding the underlying mechanism of LPA-induced ovarian cancer cell aggressiveness and providing potential biomarkers for ovarian cancer
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