Peroxisome proliferator-activated receptor-γ is downregulated in ulcerative colitis and is involved in experimental colitis-associated neoplasia

Dou,Xiaotan; Xiao,Junhua; Jin,Ziliang; Zheng,Ping

doi:10.3892/ol.2015.3397

Peroxisome proliferator-activated receptor-γ is downregulated in ulcerative colitis and is involved in experimental colitis-associated neoplasia

Authors:
- Xiaotan Dou
- Junhua Xiao
- Ziliang Jin
- Ping Zheng
View Affiliations

Affiliations: Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, Jiangsu 210000, P.R. China, Department of Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai 200085, P.R. China, Department of Oncology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai 200085, P.R. China
Published online on: June 19, 2015 https://doi.org/10.3892/ol.2015.3397
Pages: 1259-1266
Copyright: © Dou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to evaluate the expression of peroxisome proliferator-activated receptor (PPAR)-γ in inflammatory bowel disease (IBD), and to also identify the association between PPAR‑γ and the clinical features of patients with IBD. An azoxymethane (AOM)/dextran sodium sulfate (DSS) animal model of colitis‑associated neoplasia was established to investigate the protective effect of 5‑aminosalicylic acid (5‑ASA) and to explore the changes in the expression of PPAR‑γ during this process. A total of 66 specimens of colorectal tissue obtained from biopsy performed on IBD patients and 30 healthy control individuals were immunohistochemically stained for PPAR‑γ. An AOM/DSS animal model of colitis‑associated neoplasia was then established. Reverse transcription quantitative polymerase chain reaction was conducted and it was found that, compared with the control group and patients with Crohn's disease (CD), the expression of PPAR‑γ in the intestinal tissue of patients with ulcerative colitis (UC) was significantly decreased (P=0.027 and 0.046, respectively). The expression of PPAR‑γ was found to be negatively associated with the disease activity of UC and was not associated with the severity of disease, site of lesions or CD characteristics. Administration of 5‑ASA decreased the colitis and tumor burden of colons. The expression level of PPAR‑γ in the intestinal tissue was also increased in the AOM/DSS/5‑ASA group compared with AOM/DSS group (P<0.001). PPAR‑γ is an important factor in the pathogenesis of UC and colitis‑associated cancer. The present study found that 5‑ASA significantly alleviates the colitis and tumor burden in a mouse model of AOM/DSS‑induced colitis‑associated neoplasia, and promotes the expression of PPAR-γ in the intestinal tract.

View Figures

View References

1	Munkholm P: Review article: The incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther. 18:(Suppl 2). 1–5. 2003. View Article : Google Scholar : PubMed/NCBI
2	Cheng Y and Desreumaux P: 5-aminosalicylic acid is an attractive candidate agent for chemoprevention of colon cancer in patients with inflammatory bowel disease. World J Gastroenterol. 11:309–314. 2005. View Article : Google Scholar : PubMed/NCBI
3	Debril MB, Renaud JP, Fajas L and Auwerx J: The pleiotropic functions of peroxisome proliferator-activated receptor gamma. J Mol Med Berl. 79:30–47. 2001. View Article : Google Scholar : PubMed/NCBI
4	Hontecillas R and Bassaganya-Riera J: Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis. J Immunol. 178:2940–2949. 2007. View Article : Google Scholar : PubMed/NCBI
5	Schwab M, Reynders V, Loitsch S, Shastri YM, Steinhilber D, Schröder O and Stein J: PPARgamma is involved in mesalazine-mediated induction of apoptosis and inhibition of cell growth in colon cancer cells. Carcinogenesis. 29:1407–1414. 2008. View Article : Google Scholar : PubMed/NCBI
6	van Staa TP, Card T, Logan RF and Leufkens HG: 5-Aminosalicylate use and colorectal cancer risk in inflammatory bowel disease: A large epidemiological study. Gut. 54:1573–1578. 2005. View Article : Google Scholar : PubMed/NCBI
7	Rousseaux C, Lefebvre B, Dubuquoy L, Lefebvre P, Romano O, Auwerx J, Metzger D, Wahli W, Desvergne B, Naccari GC, et al: Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma. J Exp Med. 201:1205–1215. 2005. View Article : Google Scholar : PubMed/NCBI
8	Koelink PJ, Mieremet-Ooms MA, Corver WE, Wolanin K, Hommes DW, Lamers CB and Verspaget HW: 5-aminosalicylic acid interferes in the cell cycle of colorectal cancer cells and induces cell death modes. Inflamm Bowel Dis. 16:379–389. 2010. View Article : Google Scholar : PubMed/NCBI
9	Kohno H, Suzuki R, Sugie S and Tanaka T: Suppression of colitis-related mouse colon carcinogenesis by a COX-2 inhibitor and PPAR ligands. BMC Cancer. 5:462005. View Article : Google Scholar : PubMed/NCBI
10	Cooper HS, Murthy SN, Shah RS and Sedergran DJ: Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest. 69:238–249. 1993.PubMed/NCBI
11	Ni J, Chen SF and Hollander D: Effects of dextran sulphate sodium on intestinal epithelial cells and intestinal lymphocytes. Gut. 39:234–241. 1996. View Article : Google Scholar : PubMed/NCBI
12	Cooper HS, Everley L, Chang WC, Pfeiffer G, Lee B, Murthy S and Clapper ML: The role of mutant Apc in the development of dysplasia and cancer in the mouse model of dextran sulfate sodium-induced colitis. Gastroenterology. 121:1407–1416. 2001. View Article : Google Scholar : PubMed/NCBI
13	Tanaka T, Kohno H, Suzuki R, Hata K, Sugie S, Niho N, Sakano K, Takahashi M and Wakabayashi K: Dextran sodium sulfate strongly promotes colorectal carcinogenesis in Apc(Min/+) mice: Inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms. Int J Cancer. 118:25–34. 2006. View Article : Google Scholar : PubMed/NCBI
14	Murano M, Maemura K, Hirata I, Toshina K, Nishikawa T, Hamamoto N, Sasaki S, Saitoh O and Katsu K: Therapeutic effect of intracolonically administered nuclear factor kappa B (p65) antisense oligonucleotide on mouse dextran sulphate sodium (DSS)-induced colitis. Clin Exp Immunol. 120:51–58. 2000. View Article : Google Scholar : PubMed/NCBI
15	Onderdonk AB and Bartlett JG: Bacteriological studies of experimental ulcerative colitis. Am J Clin Nutr. 32:258–265. 1979.PubMed/NCBI
16	Jin Z, Jiang W, Jiao F, Hu H, Guo Z and Wang L and Wang L: Decreased expression of histone deacetylase 10 predicts poor prognosis of gastric cancer patients. Int J Clin Exp Pathol. 7:5872–5879. 2014.PubMed/NCBI
17	Dubuquoy L, Dharancy S, Nutten S, Pettersson S, Auwerx J and Desreumaux P: Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases. Lancet. 360:1410–1418. 2002. View Article : Google Scholar : PubMed/NCBI
18	Dubuquoy L, Rousseaux C, Thuru X, Peyrin-Biroulet L, Romano O, Chavatte P, Chamaillard M and Desreumaux P: PPARgamma as a new therapeutic target in inflammatory bowel diseases. Gut. 55:1341–1349. 2006. View Article : Google Scholar : PubMed/NCBI
19	Grommes C, Landreth GE and Heneka MT: Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncol. 5:419–429. 2004. View Article : Google Scholar : PubMed/NCBI
20	Chen CW, Chang YH, Tsi CJ and Lin WW: Inhibition of IFN-gamma-mediated inducible nitric oxide synthase induction by the peroxisome proliferator-activated receptor gamma agonist, 15-deoxy-delta 12,14-prostaglandin J2, involves inhibition of the upstream Janus kinase/STAT1 signaling pathway. J Immunol. 171:979–988. 2003. View Article : Google Scholar : PubMed/NCBI
21	Sánchez-Hidalgo M, Martín AR, Villegas I and Alarcón De La Lastra C: Rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma, reduces chronic colonic inflammation in rats. Biochem Pharmacol. 69:1733–1744. 2005. View Article : Google Scholar : PubMed/NCBI
22	Yang XY, Wang LH, Chen T, Hodge DR, Resau JH, DaSilva L and Farrar WL: Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma co-association with transcription factor NFAT. J Biol Chem. 275:4541–4544. 2000. View Article : Google Scholar : PubMed/NCBI
23	Krishnan A, Nair SA and Pillai MR: Biology of PPAR gamma in cancer: A critical review on existing lacunae. Curr Mol Med. 7:532–540. 2007. View Article : Google Scholar : PubMed/NCBI
24	Hontecillas R, Horne WT, Climent M, Guri AJ, Evans C, Zhang Y, Sobral BW and Bassaganya-Riera J: Immunoregulatory mechanisms of macrophage PPAR-γ in mice with experimental inflammatory bowel disease. Mucosal Immunol. 4:304–313. 2011. View Article : Google Scholar : PubMed/NCBI
25	Yamamoto-Furusho JK, Peñaloza-Coronel A, Sánchez-Muñoz F, Barreto-Zuñiga R and Dominguez-Lopez A: Peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression is downregulated in patients with active ulcerative colitis. Inflamm Bowel Dis. 17:680–681. 2011. View Article : Google Scholar : PubMed/NCBI
26	Farrell RJ and Peppercorn MA: Ulcerative colitis. Lancet. 359:331–340. 2002. View Article : Google Scholar : PubMed/NCBI
27	Ikeda I, Tomimoto A, Wada K, Fujisawa T, Fujita K, Yonemitsu K, Nozaki Y, Endo H, Takahashi H, Yoneda M, et al: 5-aminosalicylic acid given in the remission stage of colitis suppresses colitis-associated cancer in a mouse colitis model. Clin Cancer Res. 13:6527–6531. 2007. View Article : Google Scholar : PubMed/NCBI
28	Koelink PJ, Robanus-Maandag EC, Devilee P, Hommes DW, Lamers CB and Verspaget HW: 5-Aminosalicylic acid inhibits colitis-associated but not sporadic colorectal neoplasia in a novel conditional Apc mouse model. Carcinogenesis. 30:1217–1224. 2009. View Article : Google Scholar : PubMed/NCBI
29	Riddell RH, Goldman H, Ransohoff DF, Appelman HD, Fenoglio CM, Haggitt RC, Ahren C, Correa P, Hamilton SR, Morson BC, et al: Dysplasia in inflammatory bowel disease: Standardized classification with provisional clinical applications. Hum Pathol. 14:931–968. 1983. View Article : Google Scholar : PubMed/NCBI
30	Clapper ML, Gary MA, Coudry RA, Litwin S, Chang WC, Devarajan K, Lubet RA and Cooper HS: 5-aminosalicylic acid inhibits colitis-associated colorectal dysplasias in the mouse model of azoxymethane/dextran sulfate sodium-induced colitis. Inflamm Bowel Dis. 14:1341–1347. 2008. View Article : Google Scholar : PubMed/NCBI
31	Saif MW and Chu E: Biology of colorectal cancer. Cancer J. 16:196–201. 2010. View Article : Google Scholar : PubMed/NCBI
32	Liu J and Farmer SR: Regulating the balance between peroxisome proliferator-activated receptor gamma and beta-catenin signaling during adipogenesis. A glycogen synthase kinase 3beta phosphorylation-defective mutant of beta-catenin inhibits expression of a subset of adipogenic genes. J Biol Chem. 279:45020–45027. 2004. View Article : Google Scholar : PubMed/NCBI
33	Atug O, Tahan V, Eren F, Tiftikci A, Imeryuz N, Hamzaoglu HO and Tozun N: Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene in inflammatory bowel disease. J Gastrointestin Liver Dis. 17:433–437. 2008.PubMed/NCBI
34	Shrestha UK, Karimi O, Crusius JB, Zhou F, Wang Z, Chen Z, van Bodegraven AA, Xiao J, Morré SA, Wang H, et al: Distribution of peroxisome proliferator-activated receptor-gamma polymorphisms in Chinese and Dutch patients with inflammatory bowel disease. Inflamm Bowel Dis. 16:312–319. 2010. View Article : Google Scholar : PubMed/NCBI
35	Jennewein C, von Knethen A, Schmid T and Brüne B: MicroRNA-27b contributes to lipopolysaccharide-mediated peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA destabilization. J Biol Chem. 285:11846–11853. 2010. View Article : Google Scholar : PubMed/NCBI