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Invited review article| Volume 50, ISSUE 1, P1-14, April 2008

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Impact of Stat3 activation upon skin biology: A dichotomy of its role between homeostasis and diseases

      Summary

      Signal transducer and activator of transcription 3 (Stat3) is a latent cytoplasmic protein that conveys signals to the nucleus upon stimulation with IL-6, EGF, and many other cytokines/growth factors, leading to transcriptional activation of the downstream genes. It has been well defined that Stat3 plays critical roles in biological activities including cell proliferation, migration, survival, and oncogenesis. The in vivo role for Stat3 in the skin was elucidated using keratinocyte-specific Stat3 gene knockout mice, referred to as Stat3-disrutped mice. It was shown that Stat3 activation contributed to skin wound healing, keratinocyte migration, hair follicle growth, and resistance to UV irradiation-induced apoptosis. Furthermore, in the two-stage chemical carcinogenesis protocol, Stat3-disrupted mice did not develop any skin tumors. In contrast, transgenic mice with a constitutive active form of Stat3 (K5.Stat3C mice) developed squamous cell carcinoma (SCC) with a shorter latency and in much greater number compared to control mice. These results suggested a role for Stat3 not only in early stages of skin carcinogenesis but also in driving malignant progression in vivo. Moreover, Stat3 was consistently activated in epidermal keratinocytes in human psoriatic lesions, which has been assumed to recapitulate a condition of persistent wound healing reaction. Accordingly, K5.Stat3C mice were found to be psoriasis-prone. Finally, it was demonstrated that an inhibition of Stat3 activation ameliorated these pathological conditions, i.e., skin carcinogenesis and psoriasis. Here we will review the dichotomous roles for Stat3 in maintaining skin homeostasis and in the development of skin diseases such as psoriasis and skin cancer.

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      References

        • Fu X.Y.
        • Schindler C.
        • Improta T.
        • et al.
        The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction.
        Proc Natl Acad Sci USA. 1992; 89: 7840-7843
        • Schindler C.
        • Fu X.Y.
        • Improta T.
        • et al.
        Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha.
        Proc Natl Acad Sci USA. 1992; 89: 7836-7839
        • Schindler C.
        • Shuai K.
        • Prezioso V.R.
        • et al.
        Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor.
        Science. 1992; 257: 809-813
        • Darnell Jr., J.E.
        STATs and gene regulation.
        Science. 1997; 277: 1630-1635
        • Levy D.E.
        • Darnell Jr., J.E.
        Stats: transcriptional control and biological impact.
        Nat Rev Mol Cell Biol. 2002; 3: 651-662
        • Bowman T.
        • Garcia R.
        • Turkson J.
        • et al.
        STATs in oncogenesis.
        Oncogene. 2000; 19: 2474-2488
        • Bromberg J.F.
        Activation of STAT proteins and growth control.
        Bioessays. 2001; 23: 161-169
        • Bromberg J.
        Stat proteins and oncogenesis.
        J Clin Invest. 2002; 109: 1139-1142
        • Takeda K.
        • Noguchi K.
        • Shi W.
        • et al.
        Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality.
        Proc Natl Acad Sci USA. 1997; 94: 3801-3804
        • Levy D.E.
        • Lee C.K.
        What does Stat3 do?.
        J Clin Invest. 2002; 109: 1143-1148
        • Hirano T.
        • Ishihara K.
        • Hibi M.
        Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors.
        Oncogene. 2000; 19: 2548-2556
        • Bromberg J.F.
        • Wrzeszczynska M.H.
        • Devgan G.
        • et al.
        Stat3 as an oncogene.
        Cell. 1999; 98: 295-303
        • Grandis J.R.
        • Drenning S.D.
        • Zeng Q.
        • et al.
        Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo.
        Proc Natl Acad Sci USA. 2000; 97: 4227-4232
        • Leong P.L.
        • Andrews G.A.
        • Johnson D.E.
        • et al.
        Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth.
        Proc Natl Acad Sci USA. 2003; 100: 4138-4143
        • Bennett N.T.
        • Schultz G.S.
        Growth factors and wound healing: biochemical properties of growth factors and their receptors.
        Am J Surg. 1993; 165: 728-737
        • Martin P.
        Wound healing—aiming for perfect skin regeneration.
        Science. 1997; 276: 75-81
        • Coffey Jr., R.J.
        • Derynck R.
        • Wilcox J.N.
        • et al.
        Production and auto-induction of transforming growth factor-alpha in human keratinocytes.
        Nature. 1987; 328: 817-820
        • Marikovsky M.
        • Breuing K.
        • Liu P.Y.
        • et al.
        Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury.
        Proc Natl Acad Sci USA. 1993; 90: 3889-3893
        • Stoll S.
        • Garner W.
        • Elder J.
        Heparin-binding ligands mediate autocrine epidermal growth factor receptor activation in skin organ culture.
        J Clin Invest. 1997; 100: 1271-1281
        • Chen J.D.
        • Kim J.P.
        • Zhang K.
        • et al.
        Epidermal growth factor (EGF) promotes human keratinocyte locomotion on collagen by increasing the alpha 2 integrin subunit.
        Exp Cell Res. 1993; 209: 216-223
        • Pilcher B.K.
        • Dumin J.A.
        • Sudbeck B.D.
        • et al.
        The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix.
        J Cell Biol. 1997; 137: 1445-1457
        • McCawley L.J.
        • O’Brien P.
        • Hudson L.G.
        Epidermal growth factor (EGF)- and scatter factor/hepatocyte growth factor (SF/HGF)- mediated keratinocyte migration is coincident with induction of matrix metalloproteinase (MMP)-9.
        J Cell Physiol. 1998; 176: 255-265
        • Boccaccio C.
        • Ando M.
        • Tamagnone L.
        • et al.
        Induction of epithelial tubules by growth factor HGF depends on the STAT pathway.
        Nature. 1998; 391: 285-288
        • Rajewsky K.
        • Gu H.
        • Kuhn R.
        • et al.
        Conditional gene targeting.
        J Clin Invest. 1996; 98: 600-603
        • Takeda J.
        • Sano S.
        • Tarutani M.
        • et al.
        Conditional gene targeting and its application in the skin.
        J Dermatol Sci. 2000; 23: 147-154
        • Takeda K.
        • Kaisho T.
        • Yoshida N.
        • et al.
        Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice.
        J Immunol. 1998; 161: 4652-4660
        • Tarutani M.
        • Itami S.
        • Okabe M.
        • et al.
        Tissue-specific knockout of the mouse Pig-a gene reveals important roles for GPI-anchored proteins in skin development.
        Proc Natl Acad Sci USA. 1997; 94: 7400-7405
        • Sano S.
        • Itami S.
        • Takeda K.
        • et al.
        Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis.
        Embo J. 1999; 18: 4657-4668
        • Lauffenburger D.A.
        • Horwitz A.F.
        Cell migration: a physically integrated molecular process.
        Cell. 1996; 84: 359-369
        • Mitchison T.J.
        • Cramer L.P.
        Actin-based cell motility and cell locomotion.
        Cell. 1996; 84: 371-379
        • Kira M.
        • Sano S.
        • Takagi S.
        • et al.
        STAT3 deficiency in keratinocytes leads to compromised cell migration through hyperphosphorylation of p130(cas).
        J Biol Chem. 2002; 277: 12931-12936
        • Hardy M.H.
        The secret life of the hair follicle.
        Trends Genet. 1992; 8: 55-61
        • Jahoda C.A.
        • Reynolds A.J.
        Dermal-epidermal interactions. Adult follicle-derived cell populations and hair growth.
        Dermatol Clin. 1996; 14: 573-583
        • Peus D.
        • Pittelkow M.R.
        Growth factors in hair organ development and the hair growth cycle.
        Dermatol Clin. 1996; 14: 559-572
        • Wilson C.
        • Cotsarelis G.
        • Wei Z.G.
        • et al.
        Cells within the bulge region of mouse hair follicle transiently proliferate during early anagen: heterogeneity and functional differences of various hair cycles.
        Differentiation. 1994; 55: 127-136
        • Cotsarelis G.
        • Sun T.T.
        • Lavker R.M.
        Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis.
        Cell. 1990; 61: 1329-1337
        • Lindner G.
        • Menrad A.
        • Gherardi E.
        • et al.
        Involvement of hepatocyte growth factor/scatter factor and met receptor signaling in hair follicle morphogenesis and cycling.
        FASEB J. 2000; 14: 319-332
        • Taylor G.
        • Lehrer M.S.
        • Jensen P.J.
        • et al.
        Involvement of follicular stem cells in forming not only the follicle but also the epidermis.
        Cell. 2000; 102: 451-461
        • Sano S.
        • Takeda J.
        • Yoshikawa K.
        • et al.
        Tissue regeneration: hair follicle as a model.
        J Investig Dermatol Symp Proc. 2001; 6: 43-48
        • Sano S.
        • Kira M.
        • Takagi S.
        • et al.
        Two distinct signaling pathways in hair cycle induction: Stat3-dependent and -independent pathways.
        Proc Natl Acad Sci USA. 2000; 97: 13824-13829
        • DiGiovanni J.
        Multistage carcinogenesis in mouse skin.
        Pharmacol Ther. 1992; 54: 63-128
        • Chan K.S.
        • Carbajal S.
        • Kiguchi K.
        • et al.
        Epidermal growth factor receptor-mediated activation of Stat3 during multistage skin carcinogenesis.
        Cancer Res. 2004; 64: 2382-2389
        • Chan K.S.
        • Sano S.
        • Kiguchi K.
        • et al.
        Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis.
        J Clin Invest. 2004; 114: 720-728
        • Brash D.E.
        • Ziegler A.
        • Jonason A.S.
        • et al.
        Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion.
        J Investig Dermatol Symp Proc. 1996; 1: 136-142
        • Kraemer K.H.
        Sunlight and skin cancer: another link revealed.
        Proc Natl Acad Sci USA. 1997; 94: 11-14
        • Brash D.E.
        Sunlight and the onset of skin cancer.
        Trends Genet. 1997; 13: 410-414
        • de Gruijl F.R.
        • van Kranen H.J.
        • Mullenders L.H.
        UV-induced DNA damage, repair, mutations and oncogenic pathways in skin cancer.
        J Photochem Photobiol B. 2001; 63: 19-27
        • Kulms D.
        • Schwarz T.
        Molecular mechanisms of UV-induced apoptosis.
        Photodermatol Photoimmunol Photomed. 2000; 16: 195-201
        • Ziegler A.
        • Jonason A.S.
        • Leffell D.J.
        • et al.
        Sunburn and p53 in the onset of skin cancer.
        Nature. 1994; 372: 773-776
        • Hill L.L.
        • Ouhtit A.
        • Loughlin S.M.
        • et al.
        Fas ligand: a sensor for DNA damage critical in skin cancer etiology.
        Science. 1999; 285: 898-900
        • Pena J.C.
        • Fuchs E.
        • Thompson C.B.
        Bcl-x expression influences keratinocyte cell survival but not terminal differentiation.
        Cell Growth Differ. 1997; 8: 619-629
        • Mahboubi K.
        • Li F.
        • Plescia J.
        • et al.
        Interleukin-11 up-regulates survivin expression in endothelial cells through a signal transducer and activator of transcription-3 pathway.
        Lab Invest. 2001; 81: 327-334
        • Sano S.
        • Chan K.S.
        • Kira M.
        • et al.
        Signal transducer and activator of transcription 3 is a key regulator of keratinocyte survival and proliferation following UV irradiation.
        Cancer Res. 2005; 65: 5720-5729
        • Lu Y.P.
        • Lou Y.R.
        • Yen P.
        • et al.
        Time course for early adaptive responses to ultraviolet B light in the epidermis of SKH-1 mice.
        Cancer Res. 1999; 59: 4591-4602
        • Krueger J.G.
        The immunologic basis for the treatment of psoriasis with new biologic agents.
        J Am Acad Dermatol. 2002; 46 ([quiz-6]): 1-23
        • Nickoloff B.J.
        • Nestle F.O.
        Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities.
        J Clin Invest. 2004; 113: 1664-1675
        • Nickoloff B.J.
        • Stevens S.R.
        What have we learned in dermatology from the biologic therapies?.
        J Am Acad Dermatol. 2006; 54: S143-S151
        • Barker J.N.
        The pathophysiology of psoriasis.
        Lancet. 1991; 338: 227-230
        • Hertle M.D.
        • Kubler M.D.
        • Leigh I.M.
        • et al.
        Aberrant integrin expression during epidermal wound healing and in psoriatic epidermis.
        J Clin Invest. 1992; 89: 1892-1901
        • Ortonne J.P.
        Aetiology and pathogenesis of psoriasis.
        Br J Dermatol. 1996; 135: 1-5
        • Piepkorn M.
        • Pittelkow M.R.
        • Cook P.W.
        Autocrine regulation of keratinocytes: the emerging role of heparin-binding, epidermal growth factor-related growth factors.
        J Invest Dermatol. 1998; 111: 715-721
        • McKenzie R.C.
        • Sabin E.
        Aberrant signalling and transcription factor activation as an explanation for the defective growth control and differentiation of keratinocytes in psoriasis: a hypothesis.
        Exp Dermatol. 2003; 12: 337-345
        • Sano S.
        • Chan K.S.
        • Carbajal S.
        • et al.
        Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model.
        Nat Med. 2005; 11: 43-49
        • Wrone-Smith T.
        • Johnson T.
        • Nelson B.
        • et al.
        Discordant expression of Bcl-x and Bcl-2 by keratinocytes in vitro and psoriatic keratinocytes in vivo.
        Am J Pathol. 1995; 146: 1079-1088
        • Bhushan M.
        • McLaughlin B.
        • Weiss J.B.
        • et al.
        Levels of endothelial cell stimulating angiogenesis factor and vascular endothelial growth factor are elevated in psoriasis.
        Br J Dermatol. 1999; 141: 1054-1060
        • Pittelkow M.R.
        Psoriasis: more than skin deep.
        Nat Med. 2005; 11: 17-18
        • Zheng Y.
        • Danilenko D.M.
        • Valdez P.
        • et al.
        Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.
        Nature. 2007; 445: 648-651
        • Sa S.M.
        • Valdez P.A.
        • Wu J.
        • et al.
        The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
        J Immunol. 2007; 178: 2229-2240
        • Atsumi T.
        • Ishihara K.
        • Kamimura D.
        • et al.
        A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis.
        J Exp Med. 2002; 196: 979-990
        • Sawa S.
        • Kamimura D.
        • Jin G.H.
        • et al.
        Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells.
        J Exp Med. 2006; 203: 1459-1470
        • Nickoloff B.J.
        Creation of psoriatic plaques: the ultimate tumor suppressor pathway. A new model for an ancient T-cell-mediated skin disease. Viewpoint.
        J Cutan Pathol. 2001; 28: 57-64
        • Nickoloff B.J.
        The skin cancer paradox of psoriasis: a matter of life and death decisions in the epidermis.
        Arch Dermatol. 2004; 140: 873-875
        • Paltiel O.
        • Adler B.
        • Herschko K.
        • et al.
        Are patients with psoriasis susceptible to the classic risk factors for actinic keratoses?.
        Arch Dermatol. 2004; 140: 805-810

      Biography

      Shigetoshi Sano graduated and received his MD from Ehime University School of Medicine in 1983. He received his PhD degree from Osaka University School of Medicine in 1988. He worked in the Department of Microbiology and Immunology at Albert Einstein Medical College (in Dr. Barry R. Bloom's lab) as a research fellow from 1988 to 1992. He worked at the Department of Dermatology, Sakai Municipal Hospital from 1992 to 1994. He was subsequently promoted to assistant professor at the Department of Dermatology, Osaka University Graduate School of Medicine in 1992. From 2003 to 2004, he was a visiting associate professor at the Department of Carcinogenesis, University of Texas, USA. There he worked at the MD Anderson Cancer Center (in Dr. J. DiGiovanni's lab). From 2004 to 2005, he was head of the Department of Dermatology, Sumitomo Hospital, Osaka. He returned again to Department of Dermatology, Osaka University School of Medicine in 2005, and became an associate professor in 2006. Since 2007, he has been professor at the Department of Dermatology, Kochi Medical School. He won the Minami Prize in 2000, Galderma Prize in 2001, Eugene Farber Prize in 2005, and JSID Prize in 2006.