The effect of ultraviolet radiation on the transforming growth factor beta 1/Smads pathway and p53 in actinic keratosis and normal skin
- 512 Downloads
- 4 Citations
Abstract
Ultraviolet (UV) radiation is considered to be essential for the progression of actinic keratosis (AK) to squamous cell carcinoma (SCC); however, the mechanisms have not been fully elucidated. To understand this process, the effects of UV radiation on the transforming growth factor beta 1 (TGFβ1)/Smads pathway and p53 in normal skin and AK were studied. Normal human skin and AK tissues were cultured and divided into the following four groups according to the UV radiation dose: 0 (control group), 5, 10, and 20 J/cm2. The tissues were radiated for four consecutive days; 24 h after radiation, the tissues were collected for investigation. Compared with the control group, greater proliferative inhibition and apoptosis were induced by UV radiation in normal skin than AK. The expression of TGFβ1, Smad7, and p53 was increased in AK and normal skin, while the level of TβRII was decreased. Smad2 was reduced in AK only. The expressions of TβRI, Smad3, and Smad4 were not significantly changed. The results demonstrated that although p53 was induced, suppression of the TGFβ1/Smads pathway by UV radiation might contribute to the progression of AK to SCC.
Keywords
TGFβ1 Smad p53 Actinic keratosis Ultraviolet radiationAbbreviations
- AK
Actinic keratosis
- SCC
Squamous cell carcinoma
- TGFβ1
Transforming growth factor beta 1
- TβRI
Type I TGFβ receptor
- TβRII
Type II TGFβ receptor
- UV
Ultraviolet
Notes
Acknowledgments
This work was supported by a grant from the National Natural Science Foundation of China (No.: 30860257). The paper was kindly revised by Hai-Jing Yu, PhD.
References
- 1.Ashton KJ, Weinstein SR, Maguire DJ, Griffiths LR (2003) Chromosomal aberrations in squamous cell carcinoma and solar keratoses revealed by comparative genomic hybridization. Arch Dermatol 139:876–882PubMedCrossRefGoogle Scholar
- 2.Backvall H, Wassberg C, Berne B, Ponten F (2002) Similar UV responses are seen in a skin organ culture as in human skin in vivo. Exp Dermatol 11:349–356PubMedCrossRefGoogle Scholar
- 3.Benjamin CL, Ananthaswamy HN (2007) p53 and the pathogenesis of skin cancer. Toxicol Appl Pharmacol 224:241–248PubMedCrossRefGoogle Scholar
- 4.Brenner M, Degitz K, Besch R, Berking C (2005) Differential expression of melanoma-associated growth factors in keratinocytes and fibroblasts by ultraviolet A and ultraviolet B radiation. Br J Dermatol 153:733–739PubMedCrossRefGoogle Scholar
- 5.Chen YK, Yang SH, Huang AH, Hsue SS, Lin LM (2011) Aberrant expression in multiple components of the transforming growth factor-beta1-induced Smad signaling pathway during 7,12-dimethylbenz(a)anthracene-induced hamster buccal-pouch squamous-cell carcinogenesis. Oral Oncol 47:262–267PubMedCrossRefGoogle Scholar
- 6.Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, Balmain A, Akhurst RJ (1996) TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86:531–542PubMedCrossRefGoogle Scholar
- 7.Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584PubMedCrossRefGoogle Scholar
- 8.Devary Y, Gottlieb RA, Smeal T, Karin M (1992) The mammalian ultraviolet response is triggered by activation of Src tyrosine kinases. Cell 71:1081–1091PubMedCrossRefGoogle Scholar
- 9.Franzen P, ten Dijke P, Ichijo H, Yamashita H, Schulz P, Heldin CH, Miyazono K (1993) Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor. Cell 75:681–692PubMedCrossRefGoogle Scholar
- 10.Ganapathy A, Paterson IC, Prime SS, Eveson JW, Pring M, Price N, Threadgold SP, Davies M (2010) TGF-beta inhibits metastasis in late stage human squamous cell carcinoma of the skin by a mechanism that does not involve Id1. Cancer Lett 298:107–118PubMedCrossRefGoogle Scholar
- 11.Glogau RG (2000) The risk of progression to invasive disease. J Am Acad Dermatol 42:23–24PubMedCrossRefGoogle Scholar
- 12.Han G, Lu SL, Li AG, He W, Corless CL, Kulesz-Martin M, Wang XJ (2005) Distinct mechanisms of TGF-beta1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis. J Clin Invest 115:1714–1723PubMedCrossRefGoogle Scholar
- 13.Han KH, Choi HR, Won CH, Chung JH, Cho KH, Eun HC, Kim KH (2005) Alteration of the TGF-beta/SMAD pathway in intrinsically and UV-induced skin aging. Mech Ageing Dev 126:560–567PubMedCrossRefGoogle Scholar
- 14.Hasova M, Crhak T, Safrankova B, Dvorakova J, Muthny T, Velebny V, Kubala L (2011) Hyaluronan minimizes effects of UV irradiation on human keratinocytes. Arch Dermatol Res 303:277–284PubMedCrossRefGoogle Scholar
- 15.Healy E, Reynolds NJ, Smith MD, Campbell C, Farr PM, Rees JL (1994) Dissociation of erythema and p53 protein expression in human skin following UVB irradiation, and induction of p53 protein and mRNA following application of skin irritants. J Invest Dermatol 103:493–499PubMedCrossRefGoogle Scholar
- 16.Heldin CH, Miyazono K, ten Dijke P (1997) TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471PubMedCrossRefGoogle Scholar
- 17.Hill LL, Ouhtit A, Loughlin SM, Kripke ML, Ananthaswamy HN, Owen-Schaub LB (1999) Fas ligand: a sensor for DNA damage critical in skin cancer etiology. Science 285:898–900PubMedCrossRefGoogle Scholar
- 18.Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB (1992) Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 89:7491–7495PubMedCrossRefGoogle Scholar
- 19.Lee E, Yi JY, Chung E, Son Y (2010) Transforming growth factor beta (1) transactivates EGFR via an H(2)O(2)-dependent mechanism in squamous carcinoma cell line. Cancer Lett 290:43–48PubMedCrossRefGoogle Scholar
- 20.Li AG, Wang D, Feng XH, Wang XJ (2004) Latent TGFbeta1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder. EMBO J 23:1770–1781PubMedCrossRefGoogle Scholar
- 21.Lopez-Camarillo C, Ocampo EA, Casamichana ML, Perez-Plasencia C, Alvarez-Sanchez E, Marchat LA (2012) Protein kinases and transcription factors activation in response to UV-radiation of skin: implications for carcinogenesis. Int J Mol Sci 13:142–172PubMedCrossRefGoogle Scholar
- 22.Marks R, Foley P, Goodman G, Hage BH, Selwood TS (1986) Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol 115:649–655PubMedCrossRefGoogle Scholar
- 23.Massague J (2008) TGFbeta in cancer. Cell 134:215–230PubMedCrossRefGoogle Scholar
- 24.Mordasky Markell L, Perez-Lorenzo R, Masiuk KE, Kennett MJ, Glick AB (2010) Use of a TGFbeta type I receptor inhibitor in mouse skin carcinogenesis reveals a dual role for TGFbeta signaling in tumor promotion and progression. Carcinogenesis 31:2127–2135PubMedCrossRefGoogle Scholar
- 25.Mortier L, Marchetti P, Delaporte E, Martin de Lassalle E, Thomas P, Piette F, Formstecher P, Polakowska R, Danze PM (2002) Progression of actinic keratosis to squamous cell carcinoma of the skin correlates with deletion of the 9p21 region encoding the p16(INK4a) tumor suppressor. Cancer Lett 176:205–214PubMedCrossRefGoogle Scholar
- 26.Mullenders LH, Berneburg M (2001) Photoimmunology and nucleotide excision repair: impact of transcription coupled and global genome excision repair. J Photochem Photobiol B 65:97–100PubMedCrossRefGoogle Scholar
- 27.Murphy GM (2009) Ultraviolet radiation and immunosuppression. Br J Dermatol 161(Suppl 3):90–95PubMedCrossRefGoogle Scholar
- 28.Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P (1997) Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 389:631–635PubMedCrossRefGoogle Scholar
- 29.Nelson MA, Einspahr JG, Alberts DS, Balfour CA, Wymer JA, Welch KL, Salasche SJ, Bangert JL, Grogan TM, Bozzo PO (1994) Analysis of the p53 gene in human precancerous actinic keratosis lesions and squamous cell cancers. Cancer Lett 85:23–29PubMedCrossRefGoogle Scholar
- 30.Portugal-Cohen M, Soroka Y, Frusic-Zlotkin M, Verkhovsky L, Bregegere FM, Neuman R, Kohen R, Milner Y (2011) Skin organ culture as a model to study oxidative stress, inflammation and structural alterations associated with UVB-induced photodamage. Exp Dermatol 20:749–755PubMedCrossRefGoogle Scholar
- 31.Quan T, He T, Kang S, Voorhees JJ, Fisher GJ (2002) Ultraviolet irradiation alters transforming growth factor beta/Smad pathway in human skin in vivo. J Invest Dermatol 119:499–506PubMedCrossRefGoogle Scholar
- 32.Quan T, He T, Voorhees JJ, Fisher GJ (2001) Ultraviolet irradiation blocks cellular responses to transforming growth factor-beta by down-regulating its type-II receptor and inducing Smad7. J Biol Chem 276:26349–26356PubMedCrossRefGoogle Scholar
- 33.Ratushny V, Gober MD, Hick R, Ridky TW, Seykora JT (2012) From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma. J Clin Invest 122:464–472PubMedCrossRefGoogle Scholar
- 34.Roberts AB, Wakefield LM (2003) The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci USA 100:8621–8623PubMedCrossRefGoogle Scholar
- 35.Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108PubMedCrossRefGoogle Scholar
- 36.Svobodova AR, Galandakova A, Sianska J, Dolezal D, Lichnovska R, Ulrichova J, Vostalova J (2012) DNA damage after acute exposure of mice skin to physiological doses of UVB and UVA light. Arch Dermatol Res 304:407–412PubMedCrossRefGoogle Scholar
- 37.Varani J, Fay K, Perone P (2007) MDI 301, a non-irritating retinoid, induces changes in human skin that underlie repair. Arch Dermatol Res 298:439–448PubMedCrossRefGoogle Scholar
- 38.Wolber R, Schlenz K, Wakamatsu K, Smuda C, Nakanishi Y, Hearing VJ, Ito S (2008) Pigmentation effects of solar-simulated radiation as compared with UVA and UVB radiation. Pigment Cell Melanoma Res 21:487–491PubMedCrossRefGoogle Scholar
- 39.Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M (1991) Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352:345–347PubMedCrossRefGoogle Scholar