The expression of both peroxisome proliferator-activated receptor delta and cyclooxygenase-2 in tissues is associated with poor prognosis in colorectal cancer patients.
BACKGROUND
The role of peroxisome proliferator-activated receptor delta (PPAR δ) in the development and progression of colorectal cancer (CRC) remains controversial.


OBJECTIVE
We investigated the impact of PPAR δ expression in tissues on liver metastasis of CRC.


METHODS
We analyzed samples of primary CRC and matched normal adjacent tissues from 52 patients for the expression of PPAR δ, cyclooxygenase (COX)-2, vascular endothelial growth factor (VEGF)-A, and CXC chemokine receptor 4 (CXCR4). Correlations of the molecules expressions with clinical characteristics and prognosis of patients were studied.


RESULTS
The number of patients positive for PPAR δ, COX-2, CXCR4, and VEGF-A was 25, 33, 18, and 19, respectively. Among the PPAR δ (+)/COX-2 (+), PPAR δ (-)/COX-2 (+), PPAR δ (+)/COX-2 (-), and PPAR δ (-)/COX-2 (-) patient groups, PPAR δ (+)/COX-2 (+) patients had the highest incidence of liver metastasis (p<0.01). PPAR δ (+)/COX-2 (+) expression was a significant independent prognostic factor (HR=7.108, 95% CI 1.231-41.029, p=0.0283) by Cox proportional analysis. PPAR δ (+)/COX-2 (+) patients had the highest positivity for CXCR4 or VEGF-A in tissues (p<0.01). Among the patients in the CXCR4 (+)/VEGF-A (+), CXCR4 (+)/VEGF-A (-), CXCR4 (-)/VEGF-A (+), and CXCR4 (-)/VEGF-A (-) groups, CXCR4 (+)/VEGF-A (+) patients had the highest incidence of liver metastasis (p<0.01).


CONCLUSIONS
The expression of both PPAR δ and COX-2 in tissues may lead to liver metastasis and consequent poor prognosis in CRC patients.
Yoshinaga
Masahiro
M
Department of Gastroenterology, Hepatology, and Nutrition, National Hospital Organization Beppu Medical Center, 1473 Uchikamado, Beppu, Oita, 874-0011, Japan. masahiro@beppu.hosp.go.jp
Taki
Kentaro
K
Somada
Shinichi
S
Sakiyama
Yumiko
Y
Kubo
Norihiko
N
Kaku
Toyoma
T
Tsuruta
Satoru
S
Kusumoto
Tetsuya
T
Sakai
Hironori
H
Nakamura
Kazuhiko
K
Takayanagi
Ryoichi
R
Muto
Yoichi
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000378:metabolism / Q000556:secondary*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D047494:PPAR delta / Q000096:biosynthesis*; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
C527276:CXCR4 protein, human; D047494:PPAR delta; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2598-603
11226285
Oncogene. 2006 Feb 23;25(8):1225-41
16288226
J Invest Surg. 2009 Mar-Apr;22(2):105-11
19283612
Cell Cycle. 2004 Dec;3(12):1512-5
15539957
Cancer Cell. 2004 Sep;6(3):285-95
15380519
Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12890-5
17652168
J Natl Cancer Inst. 2009 May 20;101(10):762-7
19436036
Clin Cancer Res. 2000 Jul;6(7):2803-7
10914727
Cell. 1999 Oct 29;99(3):335-45
10555149
Semin Surg Oncol. 1993 May-Jun;9(3):256-63
8516614
Clin Cancer Res. 2006 May 1;12(9):2795-803
16675573
Oncol Rep. 2007 Mar;17(3):525-30
17273728
Jpn J Clin Oncol. 2007 Sep;37(9):679-85
17846040
Nat Med. 2004 May;10(5):481-3
15048110
Nat Med. 2004 Mar;10(3):245-7
14758356
Breast Cancer Res. 2003;5(5):R144-50
12927045
Int J Oncol. 2007 May;30(5):1215-22
17390024
Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13275-80
11087869
Blood. 2006 Mar 1;107(5):1761-7
16269611
Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7355-9
8041794
Methods Mol Biol. 2009;512:295-307
19347284
Exp Cell Res. 2003 Nov 1;290(2):289-302
14567988
Exp Cell Res. 2007 Oct 1;313(16):3446-58
17707368
Oncogene. 2004 Nov 25;23(55):8992-6
15480419
Br J Cancer. 2006 Oct 9;95(7):889-95
16969348
Nat Rev Cancer. 2002 Aug;2(8):563-72
12154349
Cancer Res. 2003 Apr 15;63(8):1748-51
12702555
Clin Cancer Res. 2005 Mar 1;11(5):1743-50
15755995
Neoplasia. 2009 Jul;11(7):651-61
19568410