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Overexpression and constitutive activation of PDGFs and PDGFR\u03b1 are observed in most GBM; however, available inhibitors targeting isolated signaling pathways are minimally effective. Therefore, better understanding of crucial mechanisms underlying GBM is needed for developing more effective targeted therapies.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Target genes controlled by HIF1\u03b1 in GBM were identified by analysis of TCGA database and by RNA-sequencing of GBM cells with HIF1\u03b1 knockout by sgRNA-Cas9 method. Functional roles of HIF1\u03b1, PDGFs and PDGFRs were elucidated by loss- or gain-of-function assays or chemical inhibitors, and compared in response to oxygen tension. Pharmacological efficacy and gene expression in mice with intracranial xenografts of primary GBM were analyzed by bioluminescence imaging and immunofluorescence.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>HIF1\u03b1 binds the <jats:italic>PDGFD<\/jats:italic> proximal promoter and <jats:italic>PDGFRA<\/jats:italic> intron enhancers in GBM cells under normoxia or mild-hypoxia to induce their expression and maintain constitutive activation of AKT signaling, which in turn increases HIF1\u03b1 protein level and activity. Paradoxically, severe hypoxia abrogates PDGFR\u03b1 expression despite enhancing HIF1\u03b1 accumulation and corresponding PDGF-D expression. Knockout of <jats:italic>HIF1A<\/jats:italic>, <jats:italic>PDGFD<\/jats:italic> or <jats:italic>PDGFRA<\/jats:italic> in U251 cells inhibits cell growth and invasion in vitro and eradicates tumor growth in vivo. <jats:italic>HIF1A<\/jats:italic> knockdown in primary GBM extends survival of xenograft mice, whereas <jats:italic>PDGFD<\/jats:italic> overexpression in GL261 shortens survival. HIF1\u03b1 inhibitor Echinomycin induces GBM cell apoptosis and effectively inhibits growth of GBM in vivo by simultaneously targeting HIF1\u03b1-PDGFD\/PDGFR\u03b1-AKT feedforward pathway.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>HIF1\u03b1 orchestrates expression of PDGF-D and PDGFR\u03b1 for constitutive activation of AKT pathway and is crucial for GBM malignancy. Therefore, therapies targeting HIF1\u03b1 should provide an effective treatment for GBM.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13046-021-02082-7","type":"journal-article","created":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T13:04:01Z","timestamp":1630501441000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["The HIF1\u03b1-PDGFD-PDGFR\u03b1 axis controls glioblastoma growth at normoxia\/mild-hypoxia and confers sensitivity to targeted therapy by echinomycin"],"prefix":"10.1186","volume":"40","author":[{"given":"Gong","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Bailey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoli","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingtao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqi","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,1]]},"reference":[{"issue":"10","key":"2082_CR1","doi-asserted-by":"publisher","first-page":"1985","DOI":"10.1158\/1055-9965.EPI-14-0275","volume":"23","author":"JP Thakkar","year":"2014","unstructured":"Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz-Sloan JS, et al. 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