Mapping signal transducer and activator of transcription (STAT) activity in different stages of mycosis fungoides and Sezary syndrome.
Journal
International journal of dermatology
ISSN: 1365-4632
Titre abrégé: Int J Dermatol
Pays: England
ID NLM: 0243704
Informations de publication
Date de publication:
Sep 2020
Sep 2020
Historique:
received:
06
04
2020
revised:
27
05
2020
accepted:
10
06
2020
pubmed:
10
7
2020
medline:
22
6
2021
entrez:
10
7
2020
Statut:
ppublish
Résumé
Deregulation of signal transducer and activator of transcription (STAT) signaling is known to participate in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). However, published results regarding STAT expression in different stages of CTCLs are conflicting. The aim of the study was to define the pattern of STAT expression in skin and detect any differences between pruritic and nonpruritic patients but also different stages of disease. Thirty-nine skin biopsies from CTCL patients and 24 biopsies from healthy volunteers were taken. Immunohistochemical staining for STAT 3, 5a, 5b, and 6 was performed in formalin-fixed paraffin-embedded sections of mycosis fungoides (MF) and Sezary syndrome (SS) specimens. We found increased expression of STAT proteins in CTCL: MF and SS skin in comparison to the control group. STAT5 but also STAT6 and to a lesser extent STAT3 seems to be constitutively activated in MF and SS. Moreover, also downregulation of STAT5b protein in advanced-stage CTCL appears to contribute to its pathogenesis. There were no significant associations between expression of STATs and pruritus severity. Our results confirm the possible pathogenetic role of STATs in CTCL. STATs seem to be a promising target for new effective therapeutic agents in CTCL.
Sections du résumé
BACKGROUND
BACKGROUND
Deregulation of signal transducer and activator of transcription (STAT) signaling is known to participate in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). However, published results regarding STAT expression in different stages of CTCLs are conflicting. The aim of the study was to define the pattern of STAT expression in skin and detect any differences between pruritic and nonpruritic patients but also different stages of disease.
METHODS
METHODS
Thirty-nine skin biopsies from CTCL patients and 24 biopsies from healthy volunteers were taken. Immunohistochemical staining for STAT 3, 5a, 5b, and 6 was performed in formalin-fixed paraffin-embedded sections of mycosis fungoides (MF) and Sezary syndrome (SS) specimens.
RESULTS
RESULTS
We found increased expression of STAT proteins in CTCL: MF and SS skin in comparison to the control group. STAT5 but also STAT6 and to a lesser extent STAT3 seems to be constitutively activated in MF and SS. Moreover, also downregulation of STAT5b protein in advanced-stage CTCL appears to contribute to its pathogenesis. There were no significant associations between expression of STATs and pruritus severity.
CONCLUSIONS
CONCLUSIONS
Our results confirm the possible pathogenetic role of STATs in CTCL. STATs seem to be a promising target for new effective therapeutic agents in CTCL.
Substances chimiques
STAT Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1106-1112Subventions
Organisme : Polish Ministry of Science and Higher Education
ID : 02-0066/07/253
Informations de copyright
© 2020 the International Society of Dermatology.
Références
Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768-3785.
Netchiporouk E, Litvinov IV, Moreau L, et al. Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression. Cell Cycle 2014; 13: 3331-3335.
Mitchell TJ, John S. Signal transducer and activator of transcription (STAT) signalling and T-cell lymphomas. Immunology 2005; 114: 301-312.
Juczynska K, Wozniacka A, Waszczykowska E, et al. Expression of the JAK/STAT signaling pathway in bullous pemphigoid and dermatitis herpetiformis. Mediators Inflamm 2017; 2017: 1-12.
Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT. 2013; 2: e24137.
Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9: 798-809.
Radenkovic S, Konjevic G, Gavrilovic D, et al. pSTAT3 expression associated with survival and mammographic density of breast cancer patients. Pathol Res Pract 2019; 215: 366-372.
Zhang Q, Nowak I, Vonderheid EC, et al. Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome. Proc Natl Acad Sci USA 1996; 93: 9148-9153.
Nielsen M, Kaestel CG, Eriksen KW, et al. Inhibition of constitutively activated Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis in mycosis fungoides tumor cells. Leukemia 1999; 13: 735-738.
van Kester MS, Out-Luiting JJ, von dem Borne PA, et al. Cucurbitacin I inhibits Stat3 and induces apoptosis in Sezary cells. J Invest Dermatol 2008; 128: 1691-1695.
Eriksen KW, Kaltoft K, Mikkelsen G, et al. Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells. Leukemia 2001; 15: 787-793.
Qin JZ, Kamarashev J, Zhang CL, et al. Constitutive and Interleukin-7- and Interleukin-15-Stimulated DNA binding of STAT and novel factors in cutaneous T cell lymphoma cells. J Invest Dermatol 2001; 117: 583-589.
Fantin VR, Loboda A, Paweletz CP, et al. Constitutive activation of signal transducers and activators of transcription predicts vorinostat resistance in cutaneous T-cell lymphoma. Can Res 2008; 68: 3785-3794.
Sommer VH, Clemmensen OJ, Nielsen O, et al. In vivo activation of STAT3 in cutaneous T-cell lymphoma. Evidence for an antiapoptotic function of STAT3. Leukemia 2004; 18: 1288-1295.
Litvinov IV, Cordeiro B, Fredholm S, et al. Analysis of STAT4 expression in cutaneous T-cell lymphoma (CTCL) patients and patient-derived cell lines. Cell Cycle 2014; 13: 2975-2982.
Pérez C, Mondéjar R, García-Díaz N, et al. Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-κB and nuclear factor of activated T cells pathways. Br J Dermatol 2020; 182: 147-155.
Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007; 110: 1713-1722.
Fedchenko N, Reifenrath J. Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue - a review. Diagn Pathol 2014; 9: 221.
Bromberg J. Stat proteins and oncogenesis. J Clin Invest 2001; 109: 1139-1142.
Kortylewski M, Yu H. Role of Stat3 in suppressing anti-tumor immunity. Curr Opin Immunol 2008; 20: 228-233.
Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 2007; 7: 41-51.
Kopp KL, Ralfkiaer U, Gjerdrum LM, et al. STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma. Cell Cycle 2013; 12: 1939-1947.
Litvinov IV, Pehr K, Sasseville D. Connecting the dots in cutaneous T cell lymphoma (CTCL): STAT5 regulates malignant T cell proliferation via miR-155. Cell Cycle 2013; 12: 2172-2173.
Lindahl LM, Fredholm S, Joseph C, et al. STAT5 induces miR-21 expression in cutaneous T cell lymphoma. Oncotarget 2016; 7: 45730-45744.
Wang Y, Levy DE. Comparative evolutionary genomics of the STAT family of transcription factors. JAK-STAT 2012; 1: 23-33.
Kanai T, Seki S, Jenks JA, et al. Identification of STAT5A and STAT5B target genes in human T cells. PLoS One 2014; 9: e86790.
Cui Y, Riedlinger G, Miyoshi K, et al. Inactivation of STAT5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol 2004; 24: 8037-8047.
Imada K, Bloom ET, Nakajima H, et al. STAT5B is essential for natural killer cell-mediated proliferation and cytolytic activity. J. Exp. Med 1998; 188: 2067-2074.
Villarino A, Laurence A, Robinson GW, et al. Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions. Elife 2016; 5: e08384.
Calo V, Migliavacca M, Bazan V, et al. STAT proteins: from normal control of cellular events to tumorigenesis. J Cellular Physiol 2003; 197: 157-168.
Takeda K, Akira S. STAT family of transcription factors in cytokine-mediated biological responses. Cytokine Growth Factor Rev 2000; 11: 199-207.
Nishio H, Matsui K, Tsuji H, et al. Immunolocalisation of the janus kinases (JAK)- signal transducers and activators of transcription (STAT) pathway in human epidermis. J Anat 2001; 198: 581-589.
Nadeau K, Hwa V, Rosenfeld RG. STAT5b deficiency: an unsuspected cause of growth failure, immunodeficiency, and severe pulmonary disease. J Pediatr 2011; 158: 701-708.
Kanai T, Jenks J. The STAT5b pathway defect and autoimmunity. Front Immunol 2012; 3: 234.
Lewis DJ, Huang S, Duvic M. Inflammatory cytokines and peripheral mediators in the pathophysiology of pruritus in cutaneous T-cell lymphoma. J Eur Acad Dermatol Venereol 2018; 32: 1652-1656.
Lee CH, Hong CH, Yu WT, et al. Mechanistic correlations between two itch biomarkers, cytokine interleukin-31 and neuropeptide β-endorphin, via STAT3/calcium axis in atopic dermatitis. Br J Dermatol 2012; 167(4): 794-803.
Jurisic V, Radenkovic S, Konjevic G. The actual role of LDH as tumor marker, biochemical and clinical aspects. Adv Exp Med Biol. 2015; 867: 115-124.
Chiu E, Samra B, Tam E, et al. Clinical characteristics and outcomes of caribbean patients with adult T-cell lymphoma/leukemia at two affiliated New York City Hospitals. JCO Glob Oncol. 2020; 6: 548-556.
Gao C, McCormack CJ, van der Weyden C, et al. The importance of differentiating between Mycosis Fungoides with CD30 positive large cell transformation and Mycosis Fungoides with co-existent primary cutaneous Anaplastic Large Cell Lymphoma. J Am Acad Dermatol 2020. https://doi.org/10.1016/j.jaad.2020.04.073
Dulmage B, Geskin L, Guitart J, et al. The biomarker landscape in mycosis fungoides and Sézary syndrome. Exp Dermatol 2017; 26: 668-676.
Scarisbrick JJ, Prince HM, Vermeer MH, et al. Cutaneous Lymphoma International Consortium study of outcome in advanced stages of mycosis fungoides and Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model. J Clin Oncol 2015; 33: 3766-3773.