title: Analysis of STAT4 expression in cutaneous T-cell lymphoma (CTCL) patients and patient-derived cell lines.
abstract: Deregulation of STAT signaling has been implicated in the pathogenesis for a variety of cancers, including CTCL. Recent reports indicate that loss of STAT4 expression is an important prognostic marker for CTCL progression and is associated with the acquisition of T helper 2 cell phenotype by malignant cells. However, little is known about the molecular mechanism behind the downregulation of STAT4 in this cancer. In the current work we test the expression of STAT4 and STAT6 via RT-PCR and/or Western Blot in CTCL lesional skin samples and in immortalized patient-derived cell lines. In these malignant cell lines we correlate the expression of STAT4 and STAT6 with the T helper (Th) phenotype markers and test the effect of Histone Deacetylase (HDAC) inhibitors and siRNA-mediated knock down of miR-155 on STAT4 expression. Our findings demonstrate that STAT4 expression correlates with Th1 phenotype, while STAT6 is associated with the Th2 phenotype. Our results further document that STAT4 and STAT6 genes are inversely regulated in CTCL. Treatment with HDAC inhibitors upregulates STAT4 expression, while at the same time decreases STAT6 expression in MyLa cells. Also, siRNA-mediated knock down of miR-155 leads to upregulation in STAT4 expression in MyLa cells. In summary, our results suggest that loss of STAT4 expression and associated switch to Th2 phenotype during Mycosis Fungoides progression may be driven via aberrant histone acetylation and/or upregulation of oncogenic miR-155 microRNA.
authors.affiliation: a Division of Dermatology ; McGill University Health Centre ; Montréal , QC Canada.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Litvinov
authors.forename: Brendan
authors.initials: B
authors.lastname: Cordeiro
authors.forename: Simon
authors.initials: S
authors.lastname: Fredholm
authors.forename: Niels
authors.initials: N
authors.lastname: Ødum
authors.forename: Hanieh
authors.initials: H
authors.lastname: Zargham
authors.forename: Yuanshen
authors.initials: Y
authors.lastname: Huang
authors.forename: Youwen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Kevin
authors.initials: K
authors.lastname: Pehr
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
authors.forename: Anders
authors.initials: A
authors.lastname: Woetmann
authors.forename: Denis
authors.initials: D
authors.lastname: Sasseville
mesh_terms: D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D064368:Healthy Volunteers; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D016410:Lymphoma, T-Cell, Cutaneous / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000473:pathology; D012871:Skin Diseases / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D000077337:Vorinostat; C087123:romidepsin
keywords: Abbreviations: CTCL; Cutaneous T-Cell Lymphoma (CTCL); Mycosis Fungoides (MF); STAT6 and STAT4; Sézary Syndrome (SS); cutaneous T-cell lymphoma; MF; histone deacetylase; STAT; mi-R155; mycosis fungoides; SS; signal transducers and activators of transcription.; sézary syndrome; HDAC