Abstract
Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type.
Highlights
Signal transducer and activator of transcription 3 (STAT3) is a multifunctional transcription factor involved in multiple biological processes
Constitutive activation of STAT3 has been described in head and neck squamous cell cancers (HNSCCs), where it is involved in deregulation of the cell cycle, increased cell growth, and inhibition of apoptosis [147,148,149,150]
Cellular signaling transmitted by the latter is always amplified downstream, while STAT3 translates the signal without amplification
Summary
Signal transducer and activator of transcription 3 (STAT3) is a multifunctional transcription factor involved in multiple biological processes It was identified in 1993 by Wegenka et al [1]. STATs are activated in the cytoplasm by Janus kinases (JAKs), a family composed of four different intracellular non-receptor tyrosine kinases, that transduce cytokine-mediated signals [7,8]. Recent evidence has shown that STAT3 can have opposite functions in cancer, and based on different conditions, STAT3 can act as both a potent tumor promoter and a tumor suppressor factor This appears to depend on several factors such as the integration of multiple signals, the oncogenic environment, and the alternative splicing into different isoforms
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