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The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy
Manlio Tolomeo1, Antonio Cascio1
1Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties, University of Palermo, via del Vespro 129, 90127 Palermo, Italy.
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.
Insights
Signal transducer and activator of transcription (STAT) 3 is a complex regulator. STAT3 can promote or suppress tumors depending on cellular context, requiring tailored cancer therapies.
Area of Science:
- Molecular Biology
- Cancer Biology
- Biochemistry
Background:
- Signal transducer and activator of transcription (STAT) 3 is a key transcription regulator.
- Constitutive STAT3 activation is common in many cancers, driven by factors like growth factor signaling and reduced negative regulation.
- While STAT3 mutations are infrequent, its oncogenic targets include c-myc, Bcl-2, and VEGF.
Purpose of the Study:
- To explore the multifaceted roles of STAT3 in cancer.
- To understand how cellular context and alternative splicing influence STAT3 function.
- To highlight the implications for STAT3-targeted cancer therapies.
Main Methods:
- Review of existing literature on STAT3 in cancer.
- Analysis of STAT3's oncogenic targets and regulatory mechanisms.
- Investigation of STAT3 isoforms (STAT3α and STAT3β) and their roles.
Main Results:
- STAT3 exhibits complex, context-dependent functions in tumorigenesis.
- STAT3 can act as both a tumor promoter and a tumor suppressor.
- Cellular signals, the tumor environment, and alternative splicing dictate STAT3's role.
Conclusions:
- STAT3's dual role necessitates careful consideration in cancer treatment strategies.
- Therapies targeting STAT3 must be personalized based on the specific tumor type and its molecular characteristics.
- Understanding STAT3's pleiotropic functions is crucial for effective cancer prevention and treatment.
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