Abstract
Colorectal cancer is one of the most common cancers worldwide, with an overall increased incidence annually. Despite improvements in treatment and surveillance, almost 50% develop recurrent and/or distant disease. Unknown cellular processes are the fundamental cause for treatment failure and metastatic disease. The interplay of chronic inflammation and carcinogenesis is well established. Recent work has highlighted the role of nuclear receptors and co-regulators in the inflammation to carcinogenesis process. Orphan nuclear receptors have been shown to be involved in numerous cellular processes, including both at a transcriptional and a non-genomic level. There is a significant emphasis to identify ligands that will interact and modify these nuclear receptors, with the long-term aim of developing novel pharmaceutical therapies. The identification of orphan nuclear receptor ligands will also help increase our current understanding of their role in cellular signaling, by enabling manipulation of these receptors. This review aims to provide a brief overview of some key orphan nuclear receptors which may be involved in colorectal cancer.
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References
National Cancer Intelligence Network Data Briefing, 2009. Colorectal Cancer Survival by Stage. [online] Available at http://www.ncin.org.uk/publications/data_briefings/colorectal_cancer_survival_by_stage.aspx
Rizzo A, Pallone F, Monteleone G, Fantini MC (2011) Intestinal inflammation and colorectal cancer: a double edged sword? World J Gastroenterol 17:3092–3100
Riggins RB, Mazzotta MM, Maniya OZ, Clarke R (2010) Orphan nuclear receptors in breast cancer pathogenesis and therapeutic response. Endocr Relat Cancer 17(3):213–231
Han YF, Cao GW (2012) Role of nuclear receptor NR4A2 in gastrointestinal inflammation and cancers. World J Gastroenterol 18(47):6865–6873
Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545
Lee JS, Kim KI, Baek SH (2008) Nuclear receptors and co-regulators in inflammation and cancer. Cancer Lett 267:189–196
Safe S, Kim K, Li X, Lee SO (2011) NR4A orphan receptors and cancer. Nucl Recept Signal 9:1–14
Evans RM (2005) The nuclear receptor superfamily: a rosetta stone for physiology. Mol Endocrinol 19:1429–1438
Novac N, Heinzel T (2004) Nuclear receptors: overview and classification. Curr Drug Targets Inflamm Allergy 3:335–346
Robinson-Rechavi M, Garcia HE, Laudet V (2003) The nuclear receptor superfamily. J Cell Sci 116:585–586
Zhao Y, Bruemmer D (2010) NR4A Orphan Nuclear Receptors: Transcriptional regulators of gene expression in metabolism and vascular biology. Arterioscler Thromb Vasc Biol 30(8):1535–1541
Benoit G, Malewicz M, Perlmann T (2009) Digging deep into the pockets of orphan nuclear receptors: insights from structural studies. Trends Cell Biol Chem 284:23286–23292
Gallastegui N, Mackinnon JA, Fletterick RJ, Estébanez-Perpiñá E (2015) Advances in our structural understanding of orphan nuclear receptors.Trends Biochem Sci 2015;40(1):25–35
Wu H, Lin Y, LI W, Sun Z, Gao W, Zhang H, Xie L, Jiang F, Qin B, Yan T, Chen L, Zhao Y, Cao X, Wu Y, Lin B, Zhou H, Wong AS, Zhang XK, Zeng JZ (2010) Regulation of Nurr 77 expression by beta-catenin and its mitogenic effect on colon cancer cells. FASEB J 25:192–205
Shi Y (2007) Orphan nuclear receptors in drug discovery. Drug Discov Today 12:440–445
Giguere V, Yang N, Segui P, Evans RM (1988) Identification of new class of steroid hormone receptor. Nature 331:91–94
Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM (2006) Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126:789–799
Claessens F, Gewirth DT (2004) DNA recognition by nuclear receptors. Essays Biochem 40:59–72
Freedman LP, Luisi BF, Korszun ZR, Basavappa R, Sigler PB, Yamamoto KR (1988) The function and structure of the metal coordination sites within the glucocorticoid receptor DNA binding domain. Nature 334:543–546
Zelcer N, Tontonoz P (2006) Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 116:607–614
Blumberg B, Evans RM (1998) Orphan nuclear receptors – new ligands and new possibilities. Genes Dev 12:3149–3155
Ordentlich P (2003) Identification of the antineoplastic agent 6-mercaptopurine as an activator of the orphan nuclear hormone receptor Nurr 1. J Biol Chem 278:24791–24799
Enmark E, Gustafsson JA (1996) Orphan nuclear receptors – the first eight years. Mol Endocrinol 10:1293–1307
Boute N et al (2002) The use of resonance energy transfer in high-throughput screening. BRET versus FRET. Trend Pharmacol 23:351–354
Xu HE et al (2002) Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Nature 415:813–817
Mohan HM, Aherne CM, Rogers AC, Baird AW, Winter DC, Murphy EP (2012) Molecular pathways: The role of NR4A Orphan Nuclear Receptors in Cancer. Clin Cancer Res 18:3223–3228
Hanahan D, Weinberg RA (2000) Cell 100:57–70
Martinez-Gonzalez J, Badimon L (2005) The NR4A subfamily of nuclear receptors: new early genes regulated by growth factors in vascular cells. Cardiovasc Res 65:609–618
Maxwell MA, Muscat GE (2006) The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal 4:e002
Collins D, Hogan AM, Winter DC (2011) Microbial and viral pathogens in colorectal cancer. Lancet Oncol 12(5):504–512
Hogan AM, Kennelly R, Collins D et al (2009) Oestrogen inhibits human colonic motility by a non-genomic cell membrane receptor-dependent mechanism. Br J Surg 96(7):817–822
McMorrow JP, Murphy EP (2011) Inflammation: a role for NR4A orphan nuclear receptors? Biochem Soc Trans 39(2):688–693
Holla VR, Wu H, Shi Q, Menter DG, Dubois RN (2011) Nuclear orphan receptor NR4A2; Modulates fatty acid oxidation pathways in colorectal cancer. J Biol Chem 286(34):30003–30009
Han Y, Cai H, Ma L, Ding Y, Tan X, Liu Y, Su T, Yu Y, Chang W, Zhang H, Fu C, Cao G Nuclear orphan receptor NR4A2 confers chemoresistance and predicts unfavorable prognosis of colorectal carcinoma patients who received post-operative chemotherapy. Eur. J. Cancer. 2013; Jun 25. pii: S0959–8049(13)00461–9
Li X, Tai HH (2009) Activation of thromboxane A2 receptors induces orphan nuclear receptors Nurr 1 expression and stimulates cell proliferation in human lung cancer cells. Carcinogenesis 30:1606–1613
Holla VR, Mann JR, Shi Q, Dubois RN (2006) Prostaglandin E2 regulates the nuclear receptor NR4A2 in colorectal cancer. J Biol Chem 281(5):2676–2268
Palorini R, De Rasmo D, Gaviraghi M, Danna LS, Signorile A, Cirulli C, Chiaradonna F, Alberghina L, Papa S. Oncogenic K-ras expression is associated with derangement of the cAMP/PKA pathway and forskolin-reversible alterations of mitochondrial dynamics and respiration. Oncogene 2012; 32(3):352–362
Leone V, di Palma A, Ricchi P, Acquaviva F, Giannouli M, Di Prisco AM, Iuliano F, Acquaviva AM (2007) PGE2 inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3K association and cAMP-dependant kinase A activation. Am J Physiol Gastrointest Liver Physiol 293:673–681
Zagani R, Hamzaoui N, Cacheux W, de Reynies A, Terris B, Chaussade S, Romagnolo B, Perret C, Lamarque D (2009) Cyclooxygenase-2 inhibitors down-regulate osteopontin and NR4A2 new therapeutic targets for colorectal cancers. Gastroenterology 137:1358–1366
Takamoto N, You LR, Moses K, Chiang C, Zimmer WE, Schwartz RJ, DeMayo FJ, Tsai MJ, Tsai SY (2005) COUP-TFII is essential for radial and anteroposterior patterning of the stomach. Development 132:2179–2189
Hamers AA, van Dam L, Teixeira Duarte JM et al (2015) Defiency of nuclear receptors Nurr77 aggravates mouse experimental colitis by increased NFκB activity in marcophages. PLoS One 4;10(8):e0133598. https://doi.org/10.1371/journal.pone.0133598
Liang R, Lin Y, Yuan CL, Liu ZH, Li YQ, Luo XL, Ye JZ, Ye HH (2018) High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer. Oncol Lett 15(4):5933–5939
Xiao L, Wang J, Li J, Chen X, Xu P, Sun S, He D, Cong Y, Zhai Y (2015) RORα inhibits adipocyte-conditioned medium-induced colorectal cancer cell proliferation and migration and chick embryo chorioallantoic membrane angiopoiesis. Am J Physiol Cell Physiol. 308(5):C385–96
Berman AY, Manna S, Schwartz NS, Katz YE, Sun Y, Behrmann CA, Yu JJ, Plas DR, Alayev A, Holz MK (2017) ERRα regulates the growth of triple-negative breast cancer cells via S6K1-dependent mechanism. Signal Transduct Target Ther 2:e17035
Shin D, Kim IS, Lee JM, Shin SY, Lee JH, Baek SH, Cho KH (2014) The hidden switches underlying RORα-mediated circuits that critically regulate uncontrolled cell proliferation. J Mol Cell Biol 6(4):338–348
Wen Z, Pan T, Yang S, Liu J, Tao H, Zhao Y, Xu D, Shao W, Wu J, Liu X, Wang Y, Mao J, Zhu Y (2017) Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting RORβ. Mol Cancer 16(1):20
Wang C, Zhou Y, Ruan R, Zheng M, Han W, Liao L (2015) High expression of COUP-TF II cooperated with negative Smad4 expression predicts poor prognosis in patients with colorectal cancer. Int J Clin Exp Pathol 8(6):7112–7121
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Kelly, M.E., Mohan, H.M., Baird, A.W. et al. Orphan Nuclear Receptors in Colorectal Cancer. Pathol. Oncol. Res. 24, 815–819 (2018). https://doi.org/10.1007/s12253-018-0440-6
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DOI: https://doi.org/10.1007/s12253-018-0440-6