Metastasis regulation by PPARD expression in cancer cells
Xiangsheng Zuo, Weiguo Xu, Min Xu, Rui Tian, Micheline J. Moussalli, Fei Mao, Xiaofeng Zheng, Jing Wang, Jeffrey S. Morris, Mihai Gagea, Cathy Eng, Scott Kopetz, Dipen M. Maru, Asif Rashid, Russell Broaddus, Daoyan Wei, Mien-Chie Hung, Anil K. Sood, Imad Shureiqi
Xiangsheng Zuo, Weiguo Xu, Min Xu, Rui Tian, Micheline J. Moussalli, Fei Mao, Xiaofeng Zheng, Jing Wang, Jeffrey S. Morris, Mihai Gagea, Cathy Eng, Scott Kopetz, Dipen M. Maru, Asif Rashid, Russell Broaddus, Daoyan Wei, Mien-Chie Hung, Anil K. Sood, Imad Shureiqi
View: Text | PDF
Research Article Oncology

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

Xiangsheng Zuo, Weiguo Xu, Min Xu, Rui Tian, Micheline J. Moussalli, Fei Mao, Xiaofeng Zheng, Jing Wang, Jeffrey S. Morris, Mihai Gagea, Cathy Eng, Scott Kopetz, Dipen M. Maru, Asif Rashid, Russell Broaddus, Daoyan Wei, Mien-Chie Hung, Anil K. Sood, Imad Shureiqi

×

Figure 8

PPARD in cancer cells positively regulates IL-8 expression.

Options: View larger image (or click on image) Download as PowerPoint
PPARD in cancer cells positively regulates IL-8 expression. (A and B) IL...
(A and B) IL-8 mRNA levels were measured in HCT116-WT, PPARD-KO, PPARD-KO-PD, and PPARD-KO-C cells (A) and in xenograft lung metastases from mice injected with HCT116 parental (WT) or PPARD-KO-PD cells and in the lung tissues from mice injected with HCT116 PPARD-KO or PPARD-KO-C cells as described in Figure 3, A and B (B) by qRT-PCR. (C and D) Anti–IL-8 antibody inhibits tubule formation of HUVECs. HCT116 cells stably transfected with PPARD vector or control vector were treated with either nonspecific IgG or an anti–IL-8 neutralized antibody for 72 hours, and the conditioned media were collected for a tubule formation assay. (C) Quantification of tubule formation. (D) Representative images of tubule formation. (E) HCT116 WT and PPARD-KO cells were transiently transfected with the PGL4.16 luciferase reporter vector containing the indicated IL-8 promoter regions and the pSV-β-galactosidase vector. Luciferase activity was measured 24 hours later and normalized for β-galactosidase activity. (F) PPARD binds to the IL-8 promoter to increase IL-8 expression. A 113-bp fragment of the human IL-8 promoter was amplified by qPCR, and the percent of input was used to measure the ability of PPARD to bind to the IL-8 promoter. Scale bar: 100 μm. Values in A–C, E and F are mean ± SEM. *P < 0.01, ***P < 0.0001 (2-way [A and B] or 1-way [C and F] ANOVA; unpaired t test [E]).