{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:25:57Z","timestamp":1790126757837,"version":"4.0.1"},"reference-count":61,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,6]],"date-time":"2020-09-06T00:00:00Z","timestamp":1599350400000},"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":["2019-0159"],"award-info":[{"award-number":["2019-0159"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Colorectal cancer is a significant cause of death since it frequently metastasizes to several organs such as the lung or liver. Tumor development is affected by various factors, including a tumor microenvironment, which may be an essential factor that leads to tumor growth, proliferation, invasion, and metastasis. In the tumor microenvironment, abnormal changes in various growth factors, enzymes, and cytokines can wield a strong influence on cancer. Thrombospondin-4 (THBS4), which is an extracellular matrix protein, also plays essential roles in the tumor microenvironment and mediates angiogenesis by transforming growth factor-\u03b2 (TGF\u03b2) signaling. Platelet-derived growth factor receptor \u03b2 (PDGFR\u03b2), which is a receptor tyrosine kinase and is also a downstream signal of TGF\u03b2, is associated with invasion and metastasis in colorectal cancer. We identified that PDGFR\u03b2 and THBS4 are overexpressed in tumor tissues of colorectal cancer patients, and that PDGF-D expression increased after TGF\u03b2 treatment in the colon cancer cell line DLD-1. TGF\u03b2 and PDGF-D increased cellular THBS4 protein levels and secretion but did not increase THBS4 mRNA levels. This response was further confirmed by the inositol 1,4,5-triphosphate receptor (IP3R) and stromal interaction molecule 1 (STIM1) blockade as well as the PDGFR\u03b2 blockade. We propose that the PDGFR\u03b2 signal leads to a modification of the incomplete form of THBS4 to its complete form through IP3R, STIM1, and Ca2+-signal proteins, which further induces THBS4 secretion. Additionally, we identified that DLD-1 cell-conditioned medium stimulated with PDGF-D promotes adhesion, migration, and proliferation of colon myofibroblast CCD-18co cells, and this effect was intensified in the presence of thrombin. These findings suggest that excessive PDGFR\u03b2 signaling due to increased TGF\u03b2 and PDGF-D in colorectal tumors leads to over-secretion of THBS4 and proliferative tumor development.<\/jats:p>","DOI":"10.3390\/cancers12092533","type":"journal-article","created":{"date-parts":[[2020,9,6]],"date-time":"2020-09-06T23:12:49Z","timestamp":1599433969000},"page":"2533","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Potential Role of PDGFR\u03b2-Associated THBS4 in Colorectal Cancer Development"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6671-8048","authenticated-orcid":false,"given":"Min Seob","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Physiology, Digestive Disease Research Institute, and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Seok","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Digestive Disease Research Institute, and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5823-3657","authenticated-orcid":false,"given":"Moxin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Digestive Disease Research Institute, and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JiYeon","family":"Myung","sequence":"additional","affiliation":[{"name":"Department of Physiology, Digestive Disease Research Institute, and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eui Joong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Digestive Disease Research Institute, School of Medicine, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8836-4818","authenticated-orcid":false,"given":"Yong Sung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Digestive Disease Research Institute, School of Medicine, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungil","family":"Ro","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se Eun","family":"Ha","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9359-0075","authenticated-orcid":false,"given":"Allison","family":"Bartlett","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lai","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6442-4684","authenticated-orcid":false,"given":"Han-Seung","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Digestive Disease Research Institute, School of Medicine, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suck Chei","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Digestive Disease Research Institute, School of Medicine, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won Cheol","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Surgery, Digestive Disease Research Institute, School of Medicine, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8590-3230","authenticated-orcid":false,"given":"Keun Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Surgery, Digestive Disease Research Institute, School of Medicine, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moon Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Physiology, Digestive Disease Research Institute, and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.3892\/or.2015.4108","article-title":"Genetics, diagnosis and management of colorectal cancer (Review)","volume":"34","author":"Pace","year":"2015","journal-title":"Oncol. 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