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2.
Leukemia ; 24(6): 1179-85, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20428208

ABSTRACT

Cancer often originates from a site of persistent inflammation, and the mechanisms turning chronic inflammation into a driving force of carcinogenesis are intensely investigated. Cyclooxygenase-2 (COX-2) is an inducible key modulator of inflammation that carries out the rate-limiting step in prostaglandin synthesis. Aberrant COX-2 expression and prostaglandin E(2) (PGE(2)) production have been implicated in tumorigenesis. In this study we show that COX-2 is ectopically expressed in malignant T-cell lines from patients with cutaneous T-cell lymphoma (CTCL) as well as in situ in lymphocytic cells in 21 out of 22 patients suffering from mycosis fungoides (MF) in plaque or tumor stage. COX-2 is not expressed in lymphocytes of 11 patients with patch-stage MF, whereas sporadic COX-2 staining of stromal cells is observed in the majority of patients. COX-2 expression correlates with a constitutive production of PGE(2) in malignant T cells in vitro. These cells express prostaglandin receptors EP3 and EP4 and the receptor antagonist as well as small interfering RNA (siRNA) directed against COX-2, and specific COX-2 inhibitors strongly reduce their spontaneous proliferation. In conclusion, our data indicate that COX-2 mediated PGE(2) exerts an effect as a tumor growth factor in MF.


Subject(s)
Cyclooxygenase 2/metabolism , Lymphoma, T-Cell, Cutaneous/metabolism , Mycosis Fungoides/metabolism , Prostaglandins E/pharmacology , Skin Neoplasms/metabolism , Blotting, Western , Cell Proliferation , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/genetics , Cyclooxygenase 2 Inhibitors/pharmacology , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Immunoenzyme Techniques , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/pathology , Mycosis Fungoides/drug therapy , Mycosis Fungoides/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/pharmacology , Receptors, Prostaglandin E/metabolism , Receptors, Prostaglandin E, EP3 Subtype , Reverse Transcriptase Polymerase Chain Reaction , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Tumor Cells, Cultured
3.
Leukemia ; 22(12): 2230-9, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18769452

ABSTRACT

Sézary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3 in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-beta and suppress the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-kappaB (NF-kappaB) activity in reporter assays which is in keeping with a constitutive NF-kappaB activity in the malignant T cells. In conclusion, we show that the malignant T cells express low molecular splice forms of FOXP3 and function as Tregs. Furthermore, we provide evidence that FOXP3 splice forms are functionally different from wt FOXP3 and not involved in the execution of the suppressive function. Thus, this is the first description of FOXP3 splice forms in human disease.


Subject(s)
Forkhead Transcription Factors/genetics , Sezary Syndrome/genetics , Sezary Syndrome/immunology , Skin Neoplasms/genetics , Skin Neoplasms/immunology , T-Lymphocytes, Regulatory/physiology , Adult , Aged , Alternative Splicing , Antigens, CD/metabolism , CTLA-4 Antigen , Cell Line, Tumor , Female , Forkhead Transcription Factors/metabolism , Gene Expression Regulation, Neoplastic , Humans , Immunophenotyping , Interleukin-10/metabolism , Interleukin-2 Receptor alpha Subunit/metabolism , Janus Kinase 3/metabolism , Luciferases/genetics , Male , Middle Aged , NF-kappa B/metabolism , RNA, Small Interfering , STAT5 Transcription Factor/metabolism , Sezary Syndrome/pathology , Skin Neoplasms/pathology , T-Lymphocytes, Regulatory/pathology , Transforming Growth Factor beta/metabolism
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