TY - JOUR
T1 - Metastasis regulation by PPARD expression in cancer cells
AU - Zuo, Xiangsheng
AU - Xu, Weiguo
AU - Xu, Min
AU - Tian, Rui
AU - Moussalli, Micheline J.
AU - Mao, Fei
AU - Zheng, Xiaofeng
AU - Wang, Jing
AU - Morris, Jeffrey S.
AU - Gagea, Mihai
AU - Eng, Cathy
AU - Kopetz, Scott
AU - Maru, Dipen M.
AU - Rashid, Asif
AU - Broaddus, Russell
AU - Wei, Daoyan
AU - Hung, Mien Chie
AU - Sood, Anil K.
AU - Shureiqi, Imad
N1 - Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
PY - 2017/1/12
Y1 - 2017/1/12
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.91419
DO - 10.1172/jci.insight.91419
M3 - Article
C2 - 28097239
AN - SCOPUS:85049917914
SN - 0021-9738
VL - 2
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
M1 - e91419
ER -