title: Metastasis regulation by PPARD expression in cancer cells.
abstract: Peroxisome proliferator-activated receptor-δ (PPARD) is upregulated in many major human cancers, but the role that its expression in cancer cells has in metastasis remains poorly understood. Here, we show that specific PPARD downregulation or genetic deletion of PPARD in cancer cells significantly repressed metastasis in various cancer models in vivo. Mechanistically, PPARD promoted angiogenesis via interleukin 8 in vivo and in vitro. Analysis of transcriptome profiling of HCT116 colon cancer cells with or without genetic deletion of PPARD and gene expression patterns in The Cancer Genome Atlas colorectal adenocarcinoma database identified novel pro-metastatic genes (GJA1, VIM, SPARC, STC1, SNCG) as PPARD targets. PPARD expression in cancer cells drastically affected epithelial-mesenchymal transition, migration, and invasion, further underscoring its necessity for metastasis. Clinically, high PPARD expression in various major human cancers (e.g., colorectal, lung, breast) was associated with significantly reduced metastasis-free survival. Our results demonstrate that PPARD, a druggable protein, is an important molecular target in metastatic cancer.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Zuo
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Department of Surgical Oncology, Affiliated Hospital of Hebei United University, Tangshan, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Tian
authors.affiliation: Department of Pathology.
authors.forename: Micheline J
authors.initials: MJ
authors.lastname: Moussalli
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.affiliation: Department of Bioinformatics and Computational Biology.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Bioinformatics and Computational Biology.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biostatistics.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Morris
authors.affiliation: Department of Veterinary Medicine and Surgery.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Cathy
authors.initials: C
authors.lastname: Eng
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.affiliation: Department of Pathology.
authors.forename: Dipen M
authors.initials: DM
authors.lastname: Maru
authors.affiliation: Department of Pathology.
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.affiliation: Department of Pathology.
authors.forename: Russell
authors.initials: R
authors.lastname: Broaddus
authors.affiliation: Department of Gastroenterology.
authors.forename: Daoyan
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Molecular and Cellular Oncology.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, and.|Department of Cancer Biology and.|Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Imad
authors.initials: I
authors.lastname: Shureiqi
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D015536:Down-Regulation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047494:PPAR delta / Q000235:genetics* / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D016209:Interleukin-8; D047494:PPAR delta