Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression

• Published in: Cell cycle (Georgetown, Tex.) Tex.), 2014-11, Vol.13 (21), p.3331-3335
• Main Authors: Netchiporouk, Elena, Litvinov, Ivan V, Moreau, Linda, Gilbert, Martin, Sasseville, Denis, Duvic, Madeleine
• Format: Article
• Language: English
• Subjects: and STAT6; Cutaneous T-Cell Lymphoma (CTCL); Disease Progression; Humans; Interleukin-15 - metabolism; Interleukin-2 - metabolism; Interleukin-7 - metabolism; Janus Kinase 1 - metabolism; Janus Kinase 2 - metabolism; Lymphoma, T-Cell, Cutaneous - metabolism; Lymphoma, T-Cell, Cutaneous - pathology; MicroRNAs - metabolism; Mycosis Fungoides; RNA, Messenger - metabolism; Signal Transduction; STAT Transcription Factors - metabolism; STAT3; STAT3 Transcription Factor - metabolism; STAT4; STAT4 Transcription Factor - genetics; STAT4 Transcription Factor - metabolism; STAT5; STAT5 Transcription Factor - metabolism; STAT6 Transcription Factor - metabolism; Sézary Syndrome; Th1 Cells - cytology; Th1 Cells - immunology; Th1 Cells - metabolism; Th2 Cells - cytology; Th2 Cells - immunology; Th2 Cells - metabolism
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/15384101.2014.965061

Deregulation of STAT signaling has been implicated in the pathogenesis for a variety of cancers, including CTCL. Constitutive activation of STAT5 and STAT3 was observed in early and late stages of CTCL, respectively. In early stages, IL-2, IL-7 and IL-15 signaling via JAK1 and JAK3 kinases is believed to be responsible for activating STAT5, while in advanced stages development of IL-21 autocrine signaling is thought to be important for STAT3 activation. Recent molecular evidence further suggests that upregulation of STAT5 in early disease stages results in increased expression of oncogenic miR-155 microRNA that subsequently targets STAT4 expression on mRNA level. STAT4 signaling is known to be critical for T helper (Th) 1 phenotype differentiation and its loss results in a switch from Th1 to Th2 phenotype in malignant T cells. During this switch the expression of STAT6 is often upregulated in CTCL. In advanced stages, activation of STAT3 and STAT5 may become completely cytokine-independent and be driven only via constitutively active JAK1 and JAK3 kinases. Further research into the molecular pathogenesis of JAK/STAT signaling in this cancer may enable us to develop effective therapies for our patients.