Expression of USP15, TβR-I and Smad7 in psoriasis

Abstract

The deubiquitinating enzyme ubiquitin specific peptidase 15 (USP15) is regarded as a regulator of TGFβ signaling pathway. This process depends on Smad7, the inhibitory factor of the TGFβ signal, and type I TGFβ receptor (TβR-I), one of the receptors of TGFβ. The expression level of USP15 seems to play vital roles in the pathogenesis of many neoplasms, but so far there has been no report about USP15 in psoriasis. In this study, immunohistochemical staining of USP15, TβR-I and Smad7 was performed in 30 paraffin-embedded psoriasis specimens and 10 normal specimens to investigate the expression of USP15, TβR-I and Smad7 in psoriasis and to explore the relevance among them. And USP15 small interfering RNA (USP15 siRNA) was used to transfect Hacat cells to detect the mRNA expression of TβR-I and Smad7. Of 30 cases of psoriasis in active stage, 28, 24 and 26 cases were positive for USP15, TβR-I and Smad7 staining, respectively. The positive rates of USP15 and Smad7 were significantly higher in psoriasis specimens than in normal skin specimens (44.1%±26.0% vs. 6.1%±6.6%, 47.2%±27.1% vs. 6.6%±7.1%), and positive rate of TβR-I (20.3%±22.2%) in psoriasis was lower than that in normal skin specimens (46.7%±18.2%). There was a significant positive correlation between USP15 and Smad7 expression, and significant negative correlations between USP15 and TβR-expression, an I d between TβR- and Smad7 expression I in psoriasis. After transfection of USP15 siRNA in Hacat cells, the expression of TβR-mRNA was up I -regulated and that of Smad7 was down-regulated. It is concluded that USP15 may play a role in the pathogenesis of psoriasis through regulating the TβR-I/Smad7 pathway and there may be other cell signaling pathways interacting with USP15 to take part in the development of psoriasis.

Keywords

psoriasis / USP15 / TβR-I / Smad7

References

[1] CabrijanL, LipozenčićJ, BatinacT, et al.. Psoriasis vulgaris—an inflammatory skin disease and/or benign epidermal hyperplasia. Acta Dermatovenerol Croat, 2011, 19(2): 117-119

[2] WhiteRA, MalkoskiSP, WangXJ. TGFβ signaling in head and neck squamous cell carcinoma. Oncogene, 2010, 29(40): 5437-5446

[3] FlisiakI, PorebskiP, FlisiakR, et al.. Plasma transforming growth factor beta1 as a biomarker of psoriasis activity and treatment efficacy. Biomarkers, 2003, 8(5): 437-443

[4] DoiH, ShibataMA, KiyokaneK, et al.. Downregulation of TGFbeta isoforms and their receptors contributes to keratinocyte hyperproliferation in psoriasis vulgaris. J Dermatol Sci, 2003, 33(1): 7-16

[5] YuH, MrowietzU, SeifertO. Downregulation of SMAD2, 4 and 6 mRNA and TGFbeta receptor I mRNA in lesional and non-lesional psoriatic skin. Acta Derm Venereol, 2009, 89(4): 351-356

[6] GambichlerT, TerrasS, SkryganM. TGFβ/Smad signalling in psoriatic epidermis models exposed to salt water soaks and narrowband ultraviolet B radiation. Cytokine, 2013, 64(1): 35-38

[7] YanX, ChenYG. Smad7: not only a regulator, but also a cross-talk mediator of TGF-β signalling. Biochem J, 2011, 434(1): 1-10

[8] BakerRT, WangXW, WoollattE, et al.. Identification, functional characterization, and chromosomal localization of USP15, a novel human ubiquitin-specific protease related to the UNP oncoprotein, and a systematic nomenclature for human ubiquitin-specific proteases. Genomics, 1999, 59(3): 264-274

[9] AmerikAY, HochstrasserM. Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta, 2004, 1695(1–3): 189-207

[10] EichhornPJ, RodónL, Gonzàlez-JuncàA, et al.. USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma. Nat Med, 2012, 18(3): 429-435

[11] InuiM, ManfrinA, MamidiA, et al.. USP15 is a deubiquitylating enzyme for receptor-activated SMADs. Nat Cell Biol, 2011, 13(11): 1368-1375

[12] RamakrishnaS, SureshB, BaekKH. The role of deubiquitinating enzymes in apoptosis. Cell Mol Life Sci, 2011, 68(1): 15-26

[13] BuschkeS1, StarkHJ, CerezoA, et al.. A decisive func tion of transforming growth factor-β/Smad signaling in tissue morphogenesis and differentiation of human Ha-CaT keratinocytes. Mol Biol Cell, 2011, 22(6): 782-794

[14] InmanGJ. Switching TGFβ from a tumor suppressor to a tumor promoter. Curr Opin Genet Dev, 2011, 21(1): 93-99

[15] LiAG, LuSL, HanG, et al.. Role of TGFbeta in skin inflammation and carcinogenesis. Mol Carcinog, 2006, 45(6): 389-396

[16] JoanMassagué. TGFβ in cancer. Cell, 2008, 134(2): 215-230

[17] SamantaD, DattaPK. Alterations in the Smad pathway in human cancers. Front Biosci, 2012, 17: 1281-1293

[18] LönnP, MorénA, RajaE, et al.. Regulating the stability of TGFβ receptors and Smads. Cell Res, 2009, 19(1): 21-35

[19] WrightonKH, FengXH. To (TGF)beta or not to (TGF)beta: fine-tuning of Smad signaling via post-translational modifications. Cell Signal, 2008, 20(9): 1579-1591

[20] ZiZ, ChapnickDA, LiuX. Dynamics of TGF-β/Smad signaling. FEBS Lett, 2012, 586(14): 1921-1928

[21] AggarwalK, MassaguéJ. Ubiquitin removal in the TGF-β pathway. Nat Cell Biol, 2012, 14(7): 656-657

[22] HanG, WilliamsCA, SalterK, et al.. A role for TGFbeta signaling in the pathogenesis of psoriasis. J Invest Dermatol, 2010, 130(2): 371-377