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Expression of Peroxisome Proliferator-Activated Receptor-γ in Colon Cancer: Correlation with Histopathological Parameters, Cell Cycle-Related Molecules, and Patients’ Survival

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Abstract

Peroxisome proliferator-activated receptor γ (PPAR-γ), a ligand-activated transcription factor, is a key regulator of adipogenic differentiation and glucose homeostasis. PPAR-γ ligands have recently been demonstrated to affect proliferation and differentiation in cancer cells lines. The aim of the present work was to examine PPAR-γ expression in colon cancer cases. PPAR-γ expression was examined immunohistochemically in 86 colon cancer cases and was correlated with clinicopathological parameters, tumor proliferative capacity, cell cycle-related molecule expression, and patient survival. Positive PPAR-γ immunostaining was prominent in 48 of 86 cases (56%). PPAR-γ positivity was not correlated with Dukes’ stage, histological grade of differentiation, lymph node and liver metastasis, venous invasion, tumor proliferative capacity, or patient survival. A statistically significant correlation was found between PPAR-γ and the expression of cell cycle-related molecules pRb (P < 0.016), cyclin D1 (P <0.009), p16 (P<0.032), and p21 (P<0.033), while a positive trend for cyclin E was also noted (P<0.057). The pattern, intensity, and extent of PPAR-γ expression in positive cases were not correlated with any of the examined variables. Our findings support evidence for participation of this protein in the biological mechanisms underlying carcinogenic evolution in the colon, also suggesting the importance of specific PPAR–γ ligands as cell cycle modulators for a future therapeutic approach in colon cancer.

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References

  1. Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV (1998) Ligand binding and co–activator assembly of the peroxisome proliferators activated receptor–γ. Nature 395:137–143

    Article  PubMed  CAS  Google Scholar 

  2. Willson TM, Brown PJ, Strenbach DD, Henke BR (2000) The PPARs: from orphan receptors to drug discovery. J Med Chem 43:527–550

    Article  PubMed  CAS  Google Scholar 

  3. Chawla A, Schwarz EJ, Dimaculangan DD, Lazar MA (1994) Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology 135:798–800

    Article  PubMed  CAS  Google Scholar 

  4. Braissant O, Foufelle F, Scotto C, Dauça M, Wahli W (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, β- and -γ in the adult rat. Endocrinology 137:354–366

    Article  PubMed  CAS  Google Scholar 

  5. Theocharis S, Margeli A, Vielh P, Kouraklis G (2004) Peroxisome proliferator-activated receptor–gamma ligands as cell-cycle modulators. Cancer Treat Rev 30:545–554

    Article  PubMed  CAS  Google Scholar 

  6. Fajas L, Auboeuf D, Raspe E, Shoonjans K, Lefebvre A-M, Saladin R, Najib J, Laville M, Fruchart JC, Deeb S, Vidal-Puig A, Flier J, Briggs MR, Staels B, Vidal H, Auwerx J (1997) The organization, promoter analysis and expression of the human PPARγ gene. J Biol Chem 272:18779–18789

    Article  PubMed  CAS  Google Scholar 

  7. Mukherjee R, Jow L, Croston GE, Paterniti JR (1997) Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem 272:8071–8076

    Article  PubMed  CAS  Google Scholar 

  8. Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W (2006) From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res 45:120–159

    Article  PubMed  CAS  Google Scholar 

  9. Tolon RM, Castillo AI, Aranda A (1998) Activation of the prolactin protein gene by peroxisome proliferator-activated receptor-alpha appears to be DNA binding-independent. J Biol Chem 273:26652–26661

    Article  PubMed  CAS  Google Scholar 

  10. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK (1998) The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 391:79–82

    Article  PubMed  CAS  Google Scholar 

  11. Midgley R, Kerr D (1999) Colorectal cancer. Lancet 353:391–399

    Article  PubMed  CAS  Google Scholar 

  12. Gupta RA, DuBois RN (2002) Controversy: PPAR-γ as a target for treatment of colorectal cancer. Am J Physiol 283:266–269

    Google Scholar 

  13. Bull AW (2003) The role of peroxisome proliferator-activated receptor-gamma in colon cancer and inflammatory bowel disease. Arch Pathol Lab Med 127:1121–1123

    PubMed  CAS  Google Scholar 

  14. Spiegelman BM (1998) PPARgamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 47:507–514

    Article  PubMed  CAS  Google Scholar 

  15. Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C, Spiegelman BM (1998) Differentiation reversal of malignant changes in colon cancer through PPARgamma. Nat Med 4:1946–1952

    Article  CAS  Google Scholar 

  16. Campbell SE, Stone WL, Whaley SG, Qui M, Krishnan K (2003) Gamma (γ) tocopherol upregulates peroxisome proliferator activated receptor γ expression in SW 480 human colon cancer cell lines. BMC Cancer 3:1–13

    Article  Google Scholar 

  17. Kato M, Kusumi T, Tsuchida S, Tanaka M, Sasaki M, Kudo H (2004) Induction of differentiation and peroxisome proliferator-activated receptor γ expression in colon cell lines by troglitazone. J Cancer Res Clin Oncol 130:73–79

    Article  PubMed  CAS  Google Scholar 

  18. Dubois RN, Gupta R, Brockman J, Reddy BS, Krakow SL, Lazar MA (1998) The nuclear eicosanoids receptor, PPARgamma, is aberrantly expressed in colonic cancers. Carcinogenesis 19:49–53

    Article  PubMed  CAS  Google Scholar 

  19. Matthiessen MW, Pedersen G, Albrektsen T, Adamsen S, Fleckner J, Brynskov J (2005) Peroxisome proliferator-activated receptor expression and activation in normal human colonic epithelial cells and tubular adenomas. Scand J Gastoenterol 40:198–205

    Article  CAS  Google Scholar 

  20. Su GG, Wen X, Bailey ST, Jiang W, Rangwala SM, Keilbaugh SA, Flaniqan A, Murthy S, Lazar MA, Wu GD (1999) A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. J Clin Invest 104:383–389

    PubMed  CAS  Google Scholar 

  21. Lytle C, Tod TJ, Vo KT, Lee JW, Atkinson RD, Straus DS (2005) The peroxisome proliferator-activated receptor gamma ligand rosiglitazone delays the onset of inflammatory bowel disease in mice with interleukin 10 deficiency. Inflamm Bowel Dis 11:231–243

    Article  PubMed  Google Scholar 

  22. Osawa E, Nakajima A, Wada K, Ishimine S, Fujisawa N, Kawamori T, Matsuhashi N, Kadowaki T, Ochiai M, Sekihara H, Nakagama H (2003) Peroxisome proliferator–activated receptor γ ligands suppress colon carcinogenesis induced by azoxymethane in mice. Gastroenterology 124:361–367

    Article  PubMed  CAS  Google Scholar 

  23. Kohno H, Suzuki R, Yasui Y, Hosokawa M, Miyashita K, Tanaka T (2004) Pomegranate seed oil rich in conjugated linolenic acid suppresses chemically induced colon carcinogenesis. Cancer Sci 95:481–486

    Article  PubMed  CAS  Google Scholar 

  24. Jass JR, Atkin WS, Cuzick J, Bussey HJR, Morson BC, Northover JMA, Todd IP (1986) The grading of rectal cancer. Historical perspectives and a multivariate analysis of 446 cases. Histopathology 10:437–459

    Article  PubMed  CAS  Google Scholar 

  25. Theocharis SE, Margeli A, Kanelli H, Spiliopoulou C, Manolis E, Thalhammer T, Koutselinis A (1986) Peroxisome proliferator activated receptor γ expression in two animal models of chemically induced liver injury and regeneration. Hepatology 20:A332

    Google Scholar 

  26. He T-C, Chan TA, Vogelstein B, Kinzler KW (1999) PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 99:335–345

    Article  PubMed  CAS  Google Scholar 

  27. Fajas L, Debril MB, Auwerx J (2001) Peroxisome proliferator-activated receptor-γ: from adipogenesis to carcinogenesis. J Mol Endocrinol 27:1–9

    Article  PubMed  CAS  Google Scholar 

  28. Jalving M, Koornstra JJ, De Jong S, De Vries EG, Kleibeuker JH (2005) Review article: The potential of combinational regimen with non-steroidal anti-inflammatory drugs in the chemoprevention of colorectal cancer. Aliment Pharmacol Ther 21:321–339

    Article  PubMed  CAS  Google Scholar 

  29. Han SW, Greene ME, Pitts J, Wada RK, Sidell N (2001) Novel expression and function of peroxisome proliferator-activated receptor gamma (PPARgamma) in human neuroblastoma. Clin Cancer Res 7:98–104

    PubMed  CAS  Google Scholar 

  30. Zhang GY, Ahmed N, Riley C, Oliva K, Barker G, Quinn MA, Rice GE (2005) Enhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinoma. Br J Cancer 92:113–119

    Article  PubMed  CAS  Google Scholar 

  31. Theocharis S, Kanelli H, Politi E, Margeli A, Karkandaris C, Philippides T, Koutselinis A (2002) Expression of peroxisome proliferator-activated receptor-gamma in non-small cell lung carcinoma: correlation with histological type and grade. Lung Cancer 36:249–255

    Article  PubMed  Google Scholar 

  32. Jiang WG, Redfern A, Bryce RP, Mansel RE (2000) Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action of gamma linolenic acid in breast cancer cells. Prostaglandins Leukot Essent Fatty Acids 62:119–127

    Article  PubMed  CAS  Google Scholar 

  33. Katagiri Y, Takeda K, Yu ZX, Ferrans VJ, Ozato K, Guroff G (2000) Modulation of retinoid signaling through NGF-induced nuclear export of NGFI-B. Nat Cell Biol 2:435–440

    Article  PubMed  CAS  Google Scholar 

  34. Sarraf P, Mueller E, Smith WM, Wright HM, Kum JB, Aaltonen LA, de la Chapelle A, Spiegelman BM, Eng C (1999) Loss-of-function mutations in PPARγ associated with human colon cancer. Molecular Cell 3:799–804

    Article  PubMed  CAS  Google Scholar 

  35. Wakino S, Kintscher U, Kim S, Yin F, Hsueh WA, Law RE (2000) Peroxisome proliferator-activated receptor gamma ligands inhibit retinoblastoma phosphorylation and G1→S transition in vascular smooth muscle cells. J Biol Chem 275:22435–22441

    Article  PubMed  CAS  Google Scholar 

  36. Morrison RF, Farmer SR (1999) Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18 (INK4c) and p21 (Waf1/Cip1), during adipogenesis. J Biol Chem 274:17088–17097

    Article  PubMed  CAS  Google Scholar 

  37. Yoshizumi T, Ohta T, Ninomiya I, Terada I, Fushida S, Fujimura T, Nishimura G, Shimizu K, Yi S, Miwa K (2004) Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects. Int J Oncol 25:631–639

    PubMed  CAS  Google Scholar 

  38. Kim E, Chen F, Wang CC, Harrison LE (2006) CDK5 is a novel regulatory protein in PPARgamma ligand antiproliferation. Int J Oncol 28:191–194

    PubMed  CAS  Google Scholar 

  39. Chen F, Harrison LE (2005) Ciglitazone-induced cellular anti-proliferation p27kip1 protein levels through both increased transcriptional activity and inhibition of proteasome degradation. Cell Signal 17:809–816

    Article  PubMed  CAS  Google Scholar 

  40. Yin F, Wakino S, Liu Z, Kim S, Hsueh WA, Collins AR, Van Herle AJ, Law RE (2001) Troglitazone inhibits growth of MCF-7 breast carcinoma by targeting G1 cell cycle regulators. Biochem Biophys Res Commun 286:916–922

    Article  PubMed  CAS  Google Scholar 

  41. Guan YF, Zhan YH, Breyer RM, Davis L, Breyer MD (1999) Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death. Neoplasia 1:330–339

    Article  PubMed  CAS  Google Scholar 

  42. Hupfeld CJ, Weiss RH (2001) TZDs inhibit vascular smooth muscle cell growth independently of the cyclin kinase inhibitors p21 and p27. Am J Physiol Endocrinol Metab 281:E207–E216

    PubMed  CAS  Google Scholar 

  43. Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC, Geboes K, Briggs M, Heyman R, Auwerx J (1998) Activation of peroxisome proliferator–activated receptor gamma promotes the development of colon tumors in C57BL/6J–APCMin/+mice. Nat Med 4:1053–1057

    Article  PubMed  CAS  Google Scholar 

  44. Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, Thomazy VA, Evans RM (1998) Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med 4:1058–1061

    Article  PubMed  CAS  Google Scholar 

  45. Seed B (1998) PPAR gamma and colorectal carcinoma: conflicts in a nuclear family. Nat Med 4:1004–1005

    Article  PubMed  CAS  Google Scholar 

  46. Smalley WE, Dubois RN (1997) Colorectal cancer and non steroidal antiinflammatory drugs. Adv Pharmacol 39:1–20

    Article  PubMed  CAS  Google Scholar 

  47. Prescott SM, White RL (1996) Self-promotion? Intimate connections between APC and prostaglandin H synthetase-2. Cell 87:783–786

    Article  PubMed  CAS  Google Scholar 

  48. Shiff SJ, Qiao L, Tsai LL, Rigas B (1995) Sulindac sulfide, an aspirin-like compound, inhbits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells. J Clin Invest 96:491–503

    PubMed  CAS  Google Scholar 

  49. Lim H, Gupta RA, Ma WG, Paria BC, Moller DE, Morrow JD, DuBois RN, Trzaskos JM, Dey SK (1999) Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta. Genes Dev 13:1561–1574

    PubMed  CAS  Google Scholar 

  50. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesia JP, Marco CC, McKee LJ, Bauer TL, Caro JF (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295

    Article  PubMed  CAS  Google Scholar 

  51. Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170

    Article  PubMed  CAS  Google Scholar 

  52. Giovanucci E, Willet WC (1994) Dietary factors and risk of colon cancer. Ann Med 26:443–452

    Google Scholar 

  53. Wasan HS, Novelli M, Bee J, Bodmer WF (1997) Dietary fat influences on polyp phenotype in multiple intestinal neoplasia mice. Proc Natl Acad Sci USA 94:3308–3313

    Article  PubMed  CAS  Google Scholar 

  54. Wu GD (2000) A nuclear receptor to prevent colon cancer. N Engl J Med 342:651–653

    Article  PubMed  CAS  Google Scholar 

  55. Jansson EA, Are A, Greicius G, Kuo IC, Kelly D, Arulampalam V, Pettersson S (2005) The Wnt/beta-catenin signaling pathway targets PPARgamma activity in colon cancer cells. Proc Natl Acad Sci USA 102:1460–1465

    Article  PubMed  CAS  Google Scholar 

  56. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM (1995) A prostaglandin J2 metabolite binds peroxisome proliferator–activated receptor gamma and promotes adipocyte differentiation. Cell 83:813–819

    Article  PubMed  CAS  Google Scholar 

  57. Marin HE, Peraza MA, Billin AN, Willson TM, Ward JM, Kennett MJ, Gonzalez FJ, Peters JM (2006) Ligand activation of peroxisome proliferator-activated receptor beta inhibits colon carcinogenesis. Cancer Res 66:4394–4401

    Article  PubMed  CAS  Google Scholar 

  58. Zuo X, Wu Y, Morris JS, Stimmel JB, Leesnitzer LM, Fischer SM, Lippman SM, Shureiqi I (2006) Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity. Oncogene 25:1225–1241

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Stamatios Theocharis.

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Theocharis, S., Giaginis, C., Parasi, A. et al. Expression of Peroxisome Proliferator-Activated Receptor-γ in Colon Cancer: Correlation with Histopathological Parameters, Cell Cycle-Related Molecules, and Patients’ Survival. Dig Dis Sci 52, 2305–2311 (2007). https://doi.org/10.1007/s10620-007-9794-4

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