Despite advances in radiation delivery protocols, exposure of normal tissues during the course of radiation therapy remains a limiting factor of cancer treatment. If the canonical TGF-β/Smad pathway has been extensively studied and implicated in the development of radiation damage in various organs, the precise modalities of its activation following radiation exposure remain elusive. In the present study, we hypothesized that TGF-β1 signaling and target genes expression may depend on radiation-induced modifications in Smad transcriptional co-repressors/inhibitors expressions (TGIF1, SnoN, Ski and Smad7). In endothelial cells (HUVECs) and in a model of experimental radiation enteropathy in mice, radiation exposure increases expression of TGF-β/Smad pathway and of its target gene PAI-1, together with the overexpression of Smad co-repressor TGIF1. In mice, TGIF1 deficiency is not associated with changes in the expression of radiation-induced TGF-β pathway-related transcripts following localized small intestinal irradiation. In HUVECs, TGIF1 overexpression or silencing has no influence either on the radiation-induced Smad activation or the Smad3-dependent PAI-1 overexpression. However, TGIF1 genetic deficiency sensitizes mice to radiation-induced intestinal damage after total body or localized small intestinal radiation exposure, demonstrating that TGIF1 plays a role in radiation-induced intestinal injury. In conclusion, the TGF-β/Smad co-repressor TGIF1 plays a role in radiation-induced normal tissue damage by a Smad-independent mechanism.
References
[1]
Bentzen SM (2006) Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. Nat Rev Cancer 6: 702–713.
[2]
Barnett GC, West CM, Dunning AM, Elliott RM, Coles CE, et al. (2009) Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat Rev Cancer 9: 134–142.
[3]
Denham JW, Hauer-Jensen M (2002) The radiotherapeutic injury–a complex ‘wound’. Radiother Oncol 63: 129–145.
[4]
Anscher MS (2010) Targeting the TGF-beta1 pathway to prevent normal tissue injury after cancer therapy. Oncologist 15: 350–359.
[5]
Martin M, Lefaix J, Delanian S (2000) TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys 47: 277–290.
[6]
Anscher MS, Kong FM, Jirtle RL (1998) The relevance of transforming growth factor beta 1 in pulmonary injury after radiation therapy. Lung Cancer 19: 109–120.
[7]
Robbins ME, O'Malley Y, Zhao W, Davis CS, Bonsib SM (2001) The role of the tubulointerstitium in radiation-induced renal fibrosis. Radiat Res 155: 481–489.
[8]
Wang J, Zheng H, Sung CC, Richter KK, Hauer-Jensen M (1998) Cellular sources of transforming growth factor-beta isoforms in early and chronic radiation enteropathy. Am J Pathol 153: 1531–1540.
[9]
Randall K, Coggle JE (1996) Long-term expression of transforming growth factor TGF beta 1 in mouse skin after localized beta-irradiation. Int J Radiat Biol 70: 351–360.
[10]
Anscher MS, Crocker IR, Jirtle RL (1990) Transforming growth factor-beta 1 expression in irradiated liver. Radiat Res 122: 77–85.
[11]
Kraft M, Oussoren Y, Stewart FA, Dorr W, Schultz-Hector S (1996) Radiation-induced changes in transforming growth factor beta and collagen expression in the murine bladder wall and its correlation with bladder function. Radiat Res 146: 619–627.
[12]
Milliat F, Francois A, Isoir M, Deutsch E, Tamarat R, et al. (2006) Influence of endothelial cells on vascular smooth muscle cells phenotype after irradiation: implication in radiation-induced vascular damages. Am J Pathol 169: 1484–1495.
[13]
Kruse JJ, Floot BG, te Poele JA, Russell NS, Stewart FA (2009) Radiation-induced activation of TGF-beta signaling pathways in relation to vascular damage in mouse kidneys. Radiat Res 171: 188–197.
[14]
Milliat F, Sabourin JC, Tarlet G, Holler V, Deutsch E, et al. (2008) Essential role of plasminogen activator inhibitor type-1 in radiation enteropathy. Am J Pathol 172: 691–701.
[15]
Massague J, Seoane J, Wotton D (2005) Smad transcription factors. Genes Dev 19: 2783–2810.
[16]
Scharpfenecker M, Floot B, Russell NS, Ten Dijke P, Stewart FA (2009) Endoglin haploinsufficiency reduces radiation-induced fibrosis and telangiectasia formation in mouse kidneys. Radiother Oncol 92: 484–491.
[17]
Schultze-Mosgau S, Blaese MA, Grabenbauer G, Wehrhan F, Kopp J, et al. (2004) Smad-3 and Smad-7 expression following anti-transforming growth factor beta 1 (TGFbeta1)-treatment in irradiated rat tissue. Radiother Oncol 70: 249–259.
[18]
Haydont V, Riser BL, Aigueperse J, Vozenin-Brotons MC (2008) Specific signals involved in the long-term maintenance of radiation-induced fibrogenic differentiation: a role for CCN2 and low concentration of TGF-beta1. Am J Physiol Cell Physiol 294: C1332–1341.
[19]
Flanders KC, Major CD, Arabshahi A, Aburime EE, Okada MH, et al. (2003) Interference with transforming growth factor-beta/Smad3 signaling results in accelerated healing of wounds in previously irradiated skin. Am J Pathol 163: 2247–2257.
[20]
Flanders KC, Sullivan CD, Fujii M, Sowers A, Anzano MA, et al. (2002) Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol 160: 1057–1068.
[21]
Yan X, Chen YG (2011) Smad7: not only a regulator, but also a cross-talk mediator of TGF-β signalling. Biochem J 434: 1–10.
[22]
Deheuninck J, Luo K (2009) Ski and SnoN, potent negative regulators of TGF-beta signaling. Cell Res 19: 47–57.
[23]
Wotton D, Lo RS, Lee S, Massague J (1999) A Smad transcriptional corepressor. Cell 97: 29–39.
[24]
Itoh S, ten Dijke P (2007) Negative regulation of TGF-beta receptor/Smad signal transduction. Curr Opin Cell Biol 19: 176–184.
[25]
Bartholin L, Melhuish TA, Powers SE, Goddard-Leon S, Treilleux I, et al. (2008) Maternal Tgif is required for vascularization of the embryonic placenta. Dev Biol 319: 285–297.
[26]
Aguilella C, Dubourg C, Attia-Sobol J, Vigneron J, Blayau M, et al. (2003) Molecular screening of the TGIF gene in holoprosencephaly: identification of two novel mutations. Hum Genet 112: 131–134.
[27]
Hamid R, Patterson J, Brandt SJ (2008) Genomic structure, alternative splicing and expression of TG-interacting factor, in human myeloid leukemia blasts and cell lines. Biochim Biophys Acta 1779: 347–355.
[28]
Hamid R, Brandt SJ (2009) Transforming growth-interacting factor (TGIF) regulates proliferation and differentiation of human myeloid leukemia cells. Mol Oncol 3: 451–463.
[29]
Bartholin L, Powers SE, Melhuish TA, Lasse S, Weinstein M, et al. (2006) TGIF inhibits retinoid signaling. Mol Cell Biol 26: 990–1001.
[30]
Wotton D, Lo RS, Swaby LA, Massague J (1999) Multiple modes of repression by the Smad transcriptional corepressor TGIF. J Biol Chem 274: 37105–37110.
[31]
Fukasawa H, Yamamoto T, Togawa A, Ohashi N, Fujigaki Y, et al. (2004) Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice. Proc Natl Acad Sci U S A 101: 8687–8692.
[32]
Fukasawa H, Yamamoto T, Togawa A, Ohashi N, Fujigaki Y, et al. (2006) Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury. Kidney Int 69: 1733–1740.
[33]
Huang Y, Border WA, Noble NA (2006) Perspectives on blockade of TGFbeta overexpression. Kidney Int 69: 1713–1714.
[34]
Tan R, Zhang J, Tan X, Zhang X, Yang J, et al. (2006) Downregulation of SnoN expression in obstructive nephropathy is mediated by an enhanced ubiquitin-dependent degradation. J Am Soc Nephrol 17: 2781–2791.
[35]
Mar L, Hoodless PA (2006) Embryonic fibroblasts from mice lacking Tgif were defective in cell cycling. Mol Cell Biol 26: 4302–4310.
[36]
Andarawewa KL, Paupert J, Pal A, Barcellos-Hoff MH (2007) New rationales for using TGFbeta inhibitors in radiotherapy. Int J Radiat Biol 83: 803–811.
Scharpfenecker M, Kruse JJ, Sprong D, Russell NS, Ten Dijke P, et al. (2009) Ionizing radiation shifts the PAI-1/ID-1 balance and activates notch signaling in endothelial cells. Int J Radiat Oncol Biol Phys 73: 506–513.
[39]
Ehrhart EJ, Segarini P, Tsang ML, Carroll AG, Barcellos-Hoff MH (1997) Latent transforming growth factor beta1 activation in situ: quantitative and functional evidence after low-dose gamma-irradiation. Faseb J 11: 991–1002.
[40]
Jobling MF, Mott JD, Finnegan MT, Jurukovski V, Erickson AC, et al. (2006) Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species. Radiat Res 166: 839–848.
[41]
Liu ZM, Tseng JT, Hong DY, Huang HS (2011) Suppression of TG-interacting factor sensitizes arsenic trioxide-induced apoptosis in human hepatocellular carcinoma cells. Biochem J 438: 349–358.
[42]
Seo SR, Lallemand F, Ferrand N, Pessah M, L'Hoste S, et al. (2004) The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation. Embo J 23: 3780–3792.
[43]
Melhuish TA, Wotton D (2000) The interaction of the carboxyl terminus-binding protein with the Smad corepressor TGIF is disrupted by a holoprosencephaly mutation in TGIF. J Biol Chem 275: 39762–39766.
[44]
Dai C, Liu Y (2004) Hepatocyte growth factor antagonizes the profibrotic action of TGF-beta1 in mesangial cells by stabilizing Smad transcriptional corepressor TGIF. J Am Soc Nephrol 15: 1402–1412.
[45]
Demange C, Ferrand N, Prunier C, Bourgeade MF, Atfi A (2009) A model of partnership co-opted by the homeodomain protein TGIF and the Itch/AIP4 ubiquitin ligase for effective execution of TNF-alpha cytotoxicity. Mol Cell 36: 1073–1085.
[46]
Lo RS, Wotton D, Massague J (2001) Epidermal growth factor signaling via Ras controls the Smad transcriptional co-repressor TGIF. Embo J 20: 128–136.
[47]
Chou CH, Chen SU, Cheng JC (2009) Radiation-induced interleukin-6 expression through MAPK/p38/NF-kappaB signaling pathway and the resultant antiapoptotic effect on endothelial cells through Mcl-1 expression with sIL6-Ralpha. Int J Radiat Oncol Biol Phys 75: 1553–1561.
[48]
Dent P, Yacoub A, Fisher PB, Hagan MP, Grant S (2003) MAPK pathways in radiation responses. Oncogene 22: 5885–5896.
