RETRACTED: The Role of Janus Kinase/STAT3 Pathway in Hematologic Malignancies With an Emphasis on Epigenetics

Abstract

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway has been known to be involved in cell growth, cellular differentiation processes development, immune cell survival, and hematopoietic system development. As an important member of the STAT family, STAT3 participates as a major regulator of cellular development and differentiation-associated genes. Prolonged and persistent STAT3 activation has been reported to be associated with tumor cell survival, proliferation, and invasion. Therefore, the JAK-STAT pathway can be a potential target for drug development to treat human cancers, e.g., hematological malignancies. Although STAT3 upregulation has been reported in hematopoietic cancers, protein-level STAT3 mutations have also been reported in invasive leukemias/lymphomas. The principal role of STAT3 in tumor cell growth clarifies the importance of approaches that downregulate this molecule. Epigenetic modifications are a major regulatory mechanism controlling the activity and function of STAT3. So far, several compounds have been developed to target epigenetic regulatory enzymes in blood malignancies. Here, we discuss the current knowledge about STAT3 abnormalities and carcinogenic functions in hematopoietic cancers, novel STAT3 inhibitors, the role of epigenetic mechanisms in STAT3 regulation, and targeted therapies, by focusing on STAT3-related epigenetic modifications.

Insulin/IGF Axis and the Receptor for Advanced Glycation End Products: Role in Meta-inflammation and Potential in Cancer Therapy

“…First identified when characterizing the molecular mechanisms implicated in interferon signaling, the JAK/STAT family includes 4 members of JAK (TYK2, Jak-1, Jak-2, Jak-3) and 7 members of STAT (STAT1, STAT2, STAT3, STAT4, STAT5 (a/b), STAT6), which regulate gene transcription, thereby inducing several biological responses implicated in tumorigenesis and neoplastic progression ( 233 ). JAK/STAT–mediated gene transcription is initiated when the JAK kinase domain, characterized by tyrosine catalytic activity, recruits the SH2-like domain of other JAK/STAT proteins to form homodimers or heterodimers that move in the cell nucleus to be recruited to candidate sequences within the promoter of target genes ( 233 ). Several RAGE ligands including AGEs, S100A7, HMGB-1, S100A4 have been shown to recruit the JAK/STAT signaling cascade and promote stimulatory effects in cancer.…”

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“…The authors point out the dazzling range of anticancer effects initiated by IFN-α through both direct (i.e., cell cycle arrest, apoptosis, and activation of natural killer and CD8+ T cells) and indirect (i.e., gene transcription activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway) mechanisms [ 23 ]. The JAK/STAT pathway is dysregulated in several hematologic malignancies, and this has been shown to increase the metastatic potential in animal models of melanoma, colorectal cancer, and lymphoma [ 121 ]. Defects in lymphocyte IFN signaling arise in patients with breast cancer, melanoma, and gastrointestinal cancer, and these defects may represent a common cancer-associated mechanism of immune dysfunction [ 120 ].…”

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“…Concerning recent reports, AKR1B1 suppression could constrain PGE2 activity and thus disturb cervical carcinogenesis by preventing angiogenesis and cancer cell proliferation as well as inducing apoptosis [ 160 ]. Also, CD109, as a result of its role in transforming growth factor-β1 (TGF-β1) signaling and signal transducer and activator of transcription 3 (STAT3) activation, could be an innovative target for cervical cancer therapy [ 161 – 163 ]. CD109 is drastically expressed in cervical cancer and upregulates epidermal growth factor receptor (EGFR)-mediated STAT3 phosphorylation, enabling cervical cancer cell migration and proliferation, and supporting cancer cell phenotype [ 161 ].…”