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Introduction
IL-6/JAK/STAT3 pathway
Roles of IL-6/JAK/STAT3 pathway in CRC
Modulation of IL-6/JAK/STAT3 pathway in CRC
Further perspectives
Conclusions
Introduction
Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is involved in various physiological processes, including immune function, cell growth, differentiation and hematopoiesis (1). Accumulating evidence indicates that abnormalities in the JAK/STAT3 pathway play a vital role in the oncogenesis of several cancers. It was reported (2) that constitutive activation of JAK2 was found in childhood T cell acute lymphoblastic leukemia. Constitutive activation of STAT3 is linked to cell proliferation in breast carcinoma (3) and non-small cell lung cancer (4), and also inhibits apoptosis (5). Studies have also revealed that oncogenesis can be altered by STAT3 activation (1). These published reports all demonstrate the crucial importance of the JAK/STAT3 pathway in tumorigenesis and progression.
Colorectal cancer (CRC) is the third most common cancer worldwide and it is reported that ∼530,000 patients die of the disease each year (6). Although much progress has been made in treatment, outcomes remain poor as approximately half of patients receiving treatment still die of the disease (7,8). Some studies have indicated that elevated interleukin-6 (IL-6)/JAK/STAT3 signaling is one of the key pathways involving in colorectum tumorigenesis, this signaling has a critical role in various aspects including initiation, development and formation in CRC. The role of IL-6 in tumorigenesis has been well-established in CRC. Increased production of IL-6 has been reported in tumor tissue itself and in the serum of patients with CRC (9). Recent studies show that cytokine-driven JAK/STAT3 pathways play an important role in the processes of signal transduction, which are associated with the hyperproliferative and invasive phenotype of CRC cells (10). Although our knowledge of oncogenesis, protooncogene identification and tumor suppressor genes involved in the tumorigenesis of CRC are growing, the biologic and molecular mechanisms in CRC are still poorly understood. Moreover, the molecular mechanisms that control CRC progression are related to the alteration of different proto-oncogenes, cytokines, tumor suppressor genes and their receptors (11). Notably, these abnormalities are involved in the JAK/STAT3 signal transduction pathway.
In this review, we summarize the mechanisms and roles of IL-6/JAK/STAT3 pathway in CRC and describe current therapeutic strategies to treat CRC by targeting the IL-6/JAK/STAT3 pathway. Importantly,...