Abstract
Signal transducer and activator of transcription 3 (STAT3) is an important and the most studied transcription factor in the Janus kinase (JAK)/STAT signaling pathway. STAT3 mediates the expression of various genes that play a critical role in many cellular and biological processes, such as cell proliferation, survival, differentiation, migration, angiogenesis, and inflammation. STAT3 and associated JAKs are activated and tightly regulated by a variety of cytokines and growth factors and their receptors in normal immune responses. However, abnormal expression of STAT3 leads to its constitutive activation, which promotes malignant transformation and tumor progression through oncogenic gene expression in numerous human cancers. Human lymphoma is a heterogeneous malignancy of T and B lymphocytes. Constitutive signaling by STAT3 is an oncogenic driver in several types of B-cell lymphoma and most of T-cell lymphomas. Aberrant STAT3 activation can also induce inappropriate expression of genes involved in tumor immune evasion such as PD-L1. In this review, we focus on the oncogenic role of STAT3 in human lymphoma and highlight potential therapeutic intervention by targeting JAK/STAT3 signaling.
Highlights
Signal transducer and activator of transcription 3 (STAT3) was discovered in 1993 by a biochemical study, in which STAT3 functions as an acute phase response factor and binds to its consensus DNA motif in nuclear extracts from the liver cell line HepG2 upon stimulation with the cytokine IL-6 [1].In the following year, STAT3 was molecularly cloned and further characterized as a signal transduction molecule that can be phosphorylated by signaling from receptors of the IL-6 family cytokines [2,3,4].Since STAT3 has been the most studied member of the STAT family, with a total of more than20,000 publications based on the PubMed database
We summarize the mechanisms of STAT3 activation and oncogenesis in B- and T-cell lymphomas and discuss potential therapeutic intervention
Constitutive activation of STAT3 is required for the survival and proliferation of (ABC) diffuse large B-cell lymphoma (DLBCL) cells [34]
Summary
Signal transducer and activator of transcription 3 (STAT3) was discovered in 1993 by a biochemical study, in which STAT3 functions as an acute phase response factor and binds to its consensus DNA motif in nuclear extracts from the liver cell line HepG2 upon stimulation with the cytokine IL-6 [1]. When a cytokine binds to its cognate receptor, the receptor is dimerized and phosphorylated on its intracellular tail These receptor activation events induce cross-Janus kinase (JAK) tyrosine phosphorylation and create docking sites for STAT3, where the activated JAK phosphorylates STAT3 [5,6]. STAT3, a key transcription factor in the JAK/STAT signaling pathway, regulates expression of genes that control various cellular and biological processes, including cell proliferation, survival, differentiation, migration, angiogenesis, inflammation, and immune responses [7,8]. We summarize the mechanisms of STAT3 activation and oncogenesis in B- and T-cell lymphomas and discuss potential therapeutic intervention
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