Retinoid-X-Receptors (α/β) in Melanocytes Modulate Innate Immune Responses and Differentially Regulate Cell Survival following UV Irradiation
Melanoma is the deadliest form of skin cancer. It derives from melanocytes, the melanin-producing cells of our skin, which give our skin its tone in addition to protecting it from harmful effects of ultraviolet radiation (UVR). Changes in the skin microenvironment, such as signaling from other cell types, can influence melanoma progression. While several key genes in melanoma development have been identified, the underlying mechanisms are complex; different combinations of mutations can result in melanoma formation and genetic profiles of tumors can vary greatly among patients. Therefore, identification of novel therapeutic targets is crucial. Our present study uses a tissue-specific gene ablation strategy to characterize a novel role of type II nuclear receptors [Retinoid-X-Receptors (RXRs)] in melanocytes to control UVR-induced skin immune responses and cell survival. Several of these observed changes are risk factors for melanoma progression and identify RXRs as potential drug targets for melanoma diagnosis, prevention, and treatment. This newly-discovered role of retinoid receptor signaling in immune surveillance can be studied in different types of cancer and in other diseases including metabolic syndromes and atherosclerosis. The identified pathway is ideal for targeting using specific ligands or small molecule modulators of RXR signaling in different cell types and tissues.
Vyšlo v časopise:
Retinoid-X-Receptors (α/β) in Melanocytes Modulate Innate Immune Responses and Differentially Regulate Cell Survival following UV Irradiation. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004321
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1004321
Souhrn
Melanoma is the deadliest form of skin cancer. It derives from melanocytes, the melanin-producing cells of our skin, which give our skin its tone in addition to protecting it from harmful effects of ultraviolet radiation (UVR). Changes in the skin microenvironment, such as signaling from other cell types, can influence melanoma progression. While several key genes in melanoma development have been identified, the underlying mechanisms are complex; different combinations of mutations can result in melanoma formation and genetic profiles of tumors can vary greatly among patients. Therefore, identification of novel therapeutic targets is crucial. Our present study uses a tissue-specific gene ablation strategy to characterize a novel role of type II nuclear receptors [Retinoid-X-Receptors (RXRs)] in melanocytes to control UVR-induced skin immune responses and cell survival. Several of these observed changes are risk factors for melanoma progression and identify RXRs as potential drug targets for melanoma diagnosis, prevention, and treatment. This newly-discovered role of retinoid receptor signaling in immune surveillance can be studied in different types of cancer and in other diseases including metabolic syndromes and atherosclerosis. The identified pathway is ideal for targeting using specific ligands or small molecule modulators of RXR signaling in different cell types and tissues.
Zdroje
1. ChambonP (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10: 940–954.
2. HeymanRA, MangelsdorfDJ, DyckJA, SteinRB, EicheleG, et al. (1992) 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68: 397–406.
3. LeidM, KastnerP, ChambonP (1992) Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci 17: 427–433.
4. ChakravartiN, LotanR, DiwanAH, WarnekeCL, JohnsonMM, et al. (2007) Decreased expression of retinoid receptors in melanoma: entailment in tumorigenesis and prognosis. Clin Cancer Res 13: 4817–4824.
5. HyterS, BajajG, LiangX, BarbacidM, Ganguli-IndraG, et al. (2010) Loss of nuclear receptor RXRalpha in epidermal keratinocytes promotes the formation of Cdk4-activated invasive melanomas. Pigment Cell Melanoma Res 23: 635–648.
6. WangZ, ColemanDJ, BajajG, LiangX, Ganguli-IndraG, et al. (2011) RXRalpha ablation in epidermal keratinocytes enhances UVR-induced DNA damage, apoptosis, and proliferation of keratinocytes and melanocytes. J Invest Dermatol 131: 177–187.
7. PayneAS, CorneliusLA (2002) The role of chemokines in melanoma tumor growth and metastasis. J Invest Dermatol 118: 915–922.
8. ZaidiMR, DavisS, NoonanFP, Graff-CherryC, HawleyTS, et al. (2011) Interferon-gamma links ultraviolet radiation to melanomagenesis in mice. Nature 469: 548–553.
9. DunnGP, KoebelCM, SchreiberRD (2006) Interferons, immunity and cancer immunoediting. Nat Rev Immunol 6: 836–848.
10. DigheAS, RichardsE, OldLJ, SchreiberRD (1994) Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity 1: 447–456.
11. KaplanDH, ShankaranV, DigheAS, StockertE, AguetM, et al. (1998) Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A 95: 7556–7561.
12. StreetSE, CretneyE, SmythMJ (2001) Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood 97: 192–197.
13. ZhangW, HanksAN, BoucherK, FlorellSR, AllenSM, et al. (2005) UVB-induced apoptosis drives clonal expansion during skin tumor development. Carcinogenesis 26: 249–257.
14. DelmasV, MartinozziS, BourgeoisY, HolzenbergerM, LarueL (2003) Cre-mediated recombination in the skin melanocyte lineage. Genesis 36: 73–80.
15. NissanX, LarribereL, SaidaniM, HurbainI, DelevoyeC, et al. (2011) Functional melanocytes derived from human pluripotent stem cells engraft into pluristratified epidermis. Proc Natl Acad Sci U S A 108: 14861–14866.
16. BaxterLL, PavanWJ (2002) The oculocutaneous albinism type IV gene Matp is a new marker of pigment cell precursors during mouse embryonic development. Mech Dev 116: 209–212.
17. Martinez-PomaresL, PlattN, McKnightAJ, da SilvaRP, GordonS (1996) Macrophage membrane molecules: markers of tissue differentiation and heterogeneity. Immunobiology 195: 407–416.
18. LinHH, FaunceDE, StaceyM, TerajewiczA, NakamuraT, et al. (2005) The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance. J Exp Med 201: 1615–1625.
19. DiwakarG, ZhangD, JiangS, HornyakTJ (2008) Neurofibromin as a regulator of melanocyte development and differentiation. J Cell Sci 121: 167–177.
20. Wang Z, Zhang L-j, Guha G, Li S, Kyrylkova K, et al. (2012) Selective ablation of Ctip2/Bcl11b in epidermal keratinocytes triggers atopic dermatitis-like skin inflammatory responses in adult mice. PLoS One 7: e51262.
21. LiM, IndraAK, WarotX, BrocardJ, MessaddeqN, et al. (2000) Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature 407: 633–636.
22. Savoldi-BarbosaM, Sakamoto-HojoET (2001) Influence of interferon-gamma on radiation-induced apoptosis in normal and ataxia-telangiectasia fibroblast cell lines. Teratog Carcinog Mutagen 21: 417–429.
23. TamaiM, KawakamiA, TanakaF, MiyashitaT, NakamuraH, et al. (2006) Significant inhibition of TRAIL-mediated fibroblast-like synovial cell apoptosis by IFN-gamma through JAK/STAT pathway by translational regulation. J Lab Clin Med 147: 182–190.
24. LiZ, MetzeD, NashanD, Muller-TidowC, ServeHL, et al. (2004) Expression of SOCS-1, suppressor of cytokine signalling-1, in human melanoma. J Invest Dermatol 123: 737–745.
25. SuzukiF, NankiT, ImaiT, KikuchiH, HirohataS, et al. (2005) Inhibition of CX3CL1 (fractalkine) improves experimental autoimmune myositis in SJL/J mice. J Immunol 175: 6987–6996.
26. KimCH, PelusLM, WhiteJR, ApplebaumE, JohansonK, et al. (1998) CK beta-11/macrophage inflammatory protein-3 beta/EBI1-ligand chemokine is an efficacious chemoattractant for T and B cells. J Immunol 160: 2418–2424.
27. NgoVN, TangHL, CysterJG (1998) Epstein-Barr virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissues and strongly attracts naive T cells and activated B cells. J Exp Med 188: 181–191.
28. GibejovaA, MrazekF, SubrtovaD, SekerovaV, SzotkowskaJ, et al. (2003) Expression of macrophage inflammatory protein-3 beta/CCL19 in pulmonary sarcoidosis. Am J Respir Crit Care Med 167: 1695–1703.
29. DieuMC, VanbervlietB, VicariA, BridonJM, OldhamE, et al. (1998) Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J Exp Med 188: 373–386.
30. KimCH, PelusLM, AppelbaumE, JohansonK, AnzaiN, et al. (1999) CCR7 ligands, SLC/6Ckine/Exodus2/TCA4 and CKbeta-11/MIP-3beta/ELC, are chemoattractants for CD56(+)CD16(−) NK cells and late stage lymphoid progenitors. Cell Immunol 193: 226–235.
31. KimCH, PelusLM, WhiteJR, BroxmeyerHE (1998) Macrophage-inflammatory protein-3 beta/EBI1-ligand chemokine/CK beta-11, a CC chemokine, is a chemoattractant with a specificity for macrophage progenitors among myeloid progenitor cells. J Immunol 161: 2580–2585.
32. JingH, VassiliouE, GaneaD (2003) Prostaglandin E2 inhibits production of the inflammatory chemokines CCL3 and CCL4 in dendritic cells. J Leukoc Biol 74: 868–879.
33. OteroK, VecchiA, HirschE, KearleyJ, VermiW, et al. (2010) Nonredundant role of CCRL2 in lung dendritic cell trafficking. Blood 116: 2942–2949.
34. GuanH, ZuG, XieY, TangH, JohnsonM, et al. (2003) Neuronal repellent Slit2 inhibits dendritic cell migration and the development of immune responses. J Immunol 171: 6519–6526.
35. WuJY, FengL, ParkHT, HavliogluN, WenL, et al. (2001) The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature 410: 948–952.
36. ToleS, MukovozovIM, HuangYW, MagalhaesMA, YanM, et al. (2009) The axonal repellent, Slit2, inhibits directional migration of circulating neutrophils. J Leukoc Biol 86: 1403–1415.
37. MarlowR, StricklandP, LeeJS, WuX, PebenitoM, et al. (2008) SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium. Cancer Res 68: 7819–7827.
38. KohrgruberN, GrogerM, MeranerP, KriehuberE, PetzelbauerP, et al. (2004) Plasmacytoid dendritic cell recruitment by immobilized CXCR3 ligands. J Immunol 173: 6592–6602.
39. KeeleyEC, MehradB, StrieterRM (2008) Chemokines as mediators of neovascularization. Arterioscler Thromb Vasc Biol 28: 1928–1936.
40. MehradB, KeaneMP, StrieterRM (2007) Chemokines as mediators of angiogenesis. Thromb Haemost 97: 755–762.
41. RichmondA, YangJ, SuY (2009) The good and the bad of chemokines/chemokine receptors in melanoma. Pigment Cell Melanoma Res 22: 175–186.
42. YangJ, RichmondA (2004) The angiostatic activity of interferon-inducible protein-10/CXCL10 in human melanoma depends on binding to CXCR3 but not to glycosaminoglycan. Mol Ther 9: 846–855.
43. MeloCA, DrostJ, WijchersPJ, van de WerkenH, de WitE, et al. (2013) eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol Cell 49: 524–535.
44. NaHK, KimEH, ChoiMA, ParkJM, KimDH, et al. (2012) Diallyl trisulfide induces apoptosis in human breast cancer cells through ROS-mediated activation of JNK and AP-1. Biochem Pharmacol 84: 1241–1250.
45. LiM, MessaddeqN, TeletinM, PasqualiJL, MetzgerD, et al. (2005) Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin. Proc Natl Acad Sci U S A 102: 14795–14800.
46. IndraAK, CastanedaE, AntalMC, JiangM, MessaddeqN, et al. (2007) Malignant transformation of DMBA/TPA-induced papillomas and nevi in the skin of mice selectively lacking retinoid-X-receptor alpha in epidermal keratinocytes. J Invest Dermatol 127: 1250–1260.
47. WangZ, KirkwoodJS, TaylorAW, StevensJF, LeidM, et al. (2013) Transcription factor Ctip2 controls epidermal lipid metabolism and regulates expression of genes involved in sphingolipid biosynthesis during skin development. J Invest Dermatol 133: 668–676.
48. LiangX, BhattacharyaS, BajajG, GuhaG, WangZ, et al. (2012) Delayed cutaneous wound healing and aberrant expression of hair follicle stem cell markers in mice selectively lacking Ctip2 in epidermis. PLoS One 7: e29999.
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2014 Číslo 5
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