Smad4 Loss in Mouse Keratinocytes Leads to Increased Susceptibility to UV Carcinogenesis with Reduced Ercc1-mediated DNA Repair

Overview

Journal J Invest Dermatol

Publisher Elsevier

Specialty Dermatology

Date 2013 May 8

PMID 23648546

Citations 12

Authors

Doyel Mitra

Pamela Fernandez

Li Bian

Ningjing Song

Fulun Li

Gangwen Han

Xiao-Jing Wang

Affiliations

Soon will be listed here.

Abstract

Smad4 loss occurs frequently in human skin squamous cell carcinoma (SCC), but it is unknown whether this loss increases UV-induced carcinogenesis, a major etiological factor in skin cancer. In the present study, mice with keratinocyte-specific Smad4 deletion (K14.Smad4(-/-)) and wild-type (WT) littermates were chronically UV-irradiated. Compared with WT, K14.Smad4(-/-) mice exhibited increased DNA damage and increased susceptibility to UV-induced skin cancer. Among genes involved in repairing UV-induced DNA damage, Excision repair cross-complementation group 1 (Ercc1) messenger RNA was significantly reduced in UV-treated K14.Smad4(-/-) skin compared with WT skin. Further analysis revealed that Smad4 loss confers reduced Snail binding to the Ercc1 regulatory elements, resulting in reduced Ercc1 transcription. Consistently, transient transfection of Snai1 into Smad4(-/-) keratinocytes led to increased repair of UV-induced DNA lesions. Transfection of Ercc1 into Smad4(-/-) keratinocytes restored repair of UV-induced DNA damage. Further, immunostaining revealed that the presence of Smad4 protein is associated with the presence of Snail and Ercc1 proteins in human skin SCC and precancerous actinic keratoses. Collectively, Smad4 loss-associated Snail reduction compromises Ercc1-mediated DNA repair, contributing to increased UV-induced skin carcinogenesis. Thus, we identified a role for Snail in UV-induced DNA repair.

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References

Leibeling D, Laspe P, Emmert S . Nucleotide excision repair and cancer. J Mol Histol. 2006; 37(5-7):225-38. DOI: 10.1007/s10735-006-9041-x. View

Kajita M, McClinic K, Wade P . Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol. 2004; 24(17):7559-66. PMC: 506998. DOI: 10.1128/MCB.24.17.7559-7566.2004. View

Yang L, Mao C, Teng Y, Li W, Zhang J, Cheng X . Targeted disruption of Smad4 in mouse epidermis results in failure of hair follicle cycling and formation of skin tumors. Cancer Res. 2005; 65(19):8671-8. DOI: 10.1158/0008-5472.CAN-05-0800. View

Narayanan D, Saladi R, Fox J . Ultraviolet radiation and skin cancer. Int J Dermatol. 2010; 49(9):978-86. DOI: 10.1111/j.1365-4632.2010.04474.x. View

Kawashima A, Takayama H, Kawamura N, Doi N, Sato M, Hatano K . Co-expression of ERCC1 and Snail is a prognostic but not predictive factor of cisplatin-based neoadjuvant chemotherapy for bladder cancer. Oncol Lett. 2012; 4(1):15-21. PMC: 3398367. DOI: 10.3892/ol.2012.689. View

Foster P, Dunn E, Karl K, Snir J, Nycz C, Harvey A . Cellular magnetic resonance imaging: in vivo imaging of melanoma cells in lymph nodes of mice. Neoplasia. 2008; 10(3):207-16. PMC: 2259450. DOI: 10.1593/neo.07937. View

Doig J, Anderson C, Lawrence N, Selfridge J, Brownstein D, Melton D . Mice with skin-specific DNA repair gene (Ercc1) inactivation are hypersensitive to ultraviolet irradiation-induced skin cancer and show more rapid actinic progression. Oncogene. 2006; 25(47):6229-38. DOI: 10.1038/sj.onc.1209642. View

Hoot K, Oka M, Han G, Bottinger E, Zhang Q, Wang X . HGF upregulation contributes to angiogenesis in mice with keratinocyte-specific Smad2 deletion. J Clin Invest. 2010; 120(10):3606-16. PMC: 2947237. DOI: 10.1172/JCI43304. View

Chipchase M, Melton D . The formation of UV-induced chromosome aberrations involves ERCC1 and XPF but not other nucleotide excision repair genes. DNA Repair (Amst). 2003; 1(4):335-40. DOI: 10.1016/s1568-7864(02)00010-1. View

10.

Qiao W, Li A, Owens P, Xu X, Wang X, Deng C . Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin. Oncogene. 2005; 25(2):207-17. DOI: 10.1038/sj.onc.1209029. View

11.

Aldaz C, Conti C, Klein-Szanto A, Slaga T . Progressive dysplasia and aneuploidy are hallmarks of mouse skin papillomas: relevance to malignancy. Proc Natl Acad Sci U S A. 1987; 84(7):2029-32. PMC: 304577. DOI: 10.1073/pnas.84.7.2029. View

12.

Du F, Nakamura Y, Tan T, Lee P, Lee R, Yu B . Expression of snail in epidermal keratinocytes promotes cutaneous inflammation and hyperplasia conducive to tumor formation. Cancer Res. 2010; 70(24):10080-9. PMC: 5559295. DOI: 10.1158/0008-5472.CAN-10-0324. View

13.

Olson E, Nievera C, Lee A, Chen L, Wu X . The Mre11-Rad50-Nbs1 complex acts both upstream and downstream of ataxia telangiectasia mutated and Rad3-related protein (ATR) to regulate the S-phase checkpoint following UV treatment. J Biol Chem. 2007; 282(31):22939-52. DOI: 10.1074/jbc.M702162200. View

14.

Yang X, Li C, Herrera P, Deng C . Generation of Smad4/Dpc4 conditional knockout mice. Genesis. 2002; 32(2):80-1. DOI: 10.1002/gene.10029. View

15.

Bornstein S, White R, Malkoski S, Oka M, Han G, Cleaver T . Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J Clin Invest. 2009; 119(11):3408-19. PMC: 2769185. DOI: 10.1172/JCI38854. View

16.

Hsu D, Lan H, Huang C, Tai S, Chang S, Tsai T . Regulation of excision repair cross-complementation group 1 by Snail contributes to cisplatin resistance in head and neck cancer. Clin Cancer Res. 2010; 16(18):4561-71. DOI: 10.1158/1078-0432.CCR-10-0593. View

17.

Han G, Li A, Liang Y, Owens P, He W, Lu S . Smad7-induced beta-catenin degradation alters epidermal appendage development. Dev Cell. 2006; 11(3):301-12. DOI: 10.1016/j.devcel.2006.06.014. View

18.

Hanasoge S, Ljungman M . H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase. Carcinogenesis. 2007; 28(11):2298-304. DOI: 10.1093/carcin/bgm157. View

19.

Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J . The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000; 2(2):84-9. DOI: 10.1038/35000034. View

20.

Kraemer K, Lee M, Scotto J . Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol. 1987; 123(2):241-50. DOI: 10.1001/archderm.123.2.241. View