Metastasis regulation by PPARD expression in cancer cells
Xiangsheng Zuo, … , Anil K. Sood, Imad Shureiqi
Xiangsheng Zuo, … , Anil K. Sood, Imad Shureiqi
Published January 12, 2017
Citation Information: JCI Insight. 2017;2(1):e91419. https://doi.org/10.1172/jci.insight.91419.
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 6

PPARD expression in cancer cells promotes angiogenesis in vivo and in vitro.

Options: View larger image (or click on image) Download as PowerPoint
PPARD expression in cancer cells promotes angiogenesis in vivo and in vi...
(A–F) PPARD downregulation in cancer cells inhibits angiogenesis in vivo. (A and B) Lung metastases were formed as described in Figure 1, A and B, harvested in optimum cutting temperature compound (OCT), and assessed for the microvessel density (MVD) marker CD31 by IHC staining. (A) Representative images of IHC staining of CD31. (B) Quantification of MVD. (C and D) Lung metastases were formed as described in Figure 2, A and B, harvested in OCT, and assessed for CD31 by IHC staining. (C) Representative images of IHC staining of CD31. (D) Quantification of MVD. (E and F) Lung metastases were formed as described in Figure 5, harvested in OCT, and assessed for CD31 by IHC staining. (E) Representative images of IHC staining of CD31. (F) Quantification of MVD. Green arrows indicate tumor blood vessels. Values in B, D, and F are mean ± SEM; *P < 0.01; #P < 0.001 compared with control-shRNA group. P values were calculated by 1-way (B and D) or 2-way ANOVA (F). (G and H) PPARD overexpression in colon cancer cells promotes angiogenesis in vitro. HCT116 cells stably transfected with PPARD vector or control vector were cultured in serum-free medium for 48 hours, and the conditioned media were collected for tubule formation assay using HUVECs. (G) Representative images of tubule formation. (H) Quantification of tubule formation. (I and J) The PPARD agonist GW0742 increases tubule formation by HUVECs. HCT116 cells were treated with the PPARD agonist GW0742 (1 μM) or the control solvent (DMSO) in serum-free medium for 72 hours, and the conditioned media were collected for the tubule formation assay. (I) Representative images of tubule formation. (J) Quantification of tubule formation. The values in H and J are mean ± SEM. *P < 0.01; **P < 0.001 (unpaired t test). All scale bars: 100 μm.