{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T15:42:41Z","timestamp":1764603761533,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T00:00:00Z","timestamp":1621468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2017R1E1A1A01074091"],"award-info":[{"award-number":["2017R1E1A1A01074091"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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-1\u03b1, 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-1\u03b1 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-1\u03b1\/Twist1 signaling axes, aggravating ovarian cancer cell invasion.<\/jats:p>","DOI":"10.3390\/ijms22105374","type":"journal-article","created":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T11:45:57Z","timestamp":1621511157000},"page":"5374","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer Aggressiveness"],"prefix":"10.3390","volume":"22","author":[{"given":"Bo Young","family":"Jeong","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyung Hwa","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Se-Hee","family":"Yoon","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Department of Internal Medicine, College of Medicine, Daejeon 35365, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang Gyo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8029-2004","authenticated-orcid":false,"given":"Hwan-Woo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, College of Medicine, Konyang University, Daejeon 35365, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hoi Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S1535-6108(04)00002-9","article-title":"Focus on epithelial ovarian cancer","volume":"5","author":"Ozols","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/s11764-016-0564-1","article-title":"Evaluation and treatment of insomnia in adult cancer survivorship programs","volume":"11","author":"Zhou","year":"2017","journal-title":"J. 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