Abstract

The roles and significance of STAT3 in cancer biology have been extensively studied for more than a decade. Mounting evidence has shown that constitutive activation of STAT3 is a frequent biochemical aberrancy in cancer cells, and this abnormality directly contributes to tumorigenesis and shapes many malignant phenotypes in cancer cells. Nevertheless, results from more recent experimental and clinicopathologic studies have suggested that STAT3 also can exert tumor suppressor effects under specific conditions. Importantly, some of these studies have demonstrated that STAT3 can function either as an oncoprotein or a tumor suppressor in the same cell type, depending on the specific genetic background or presence/absence of specific coexisting biochemical defects. Thus, in the context of cancer biology, STAT3 can be a friend or foe. In the first half of this review, we will highlight the “evil” features of STAT3 by summarizing its oncogenic functions and mechanisms. The differences between the canonical and non-canonical pathway will be highlighted. In the second half, we will summarize the evidence supporting that STAT3 can function as a tumor suppressor. To explain how STAT3 may mediate its tumor suppressor effects, we will discuss several possible mechanisms, one of which is linked to the role of STAT3β, one of the two STAT3 splicing isoforms. Taken together, it is clear that the roles of STAT3 in cancer are multi-faceted and far more complicated than one appreciated previously. The new knowledge has provided us with new approaches and strategies when we evaluate STAT3 as a prognostic biomarker or therapeutic target.

Highlights

  • The roles and significance of STAT3 in cancer biology have been extensively studied for more than a decade

  • While these discrepancies may be partly attributed to the use of slightly different immunohistochemical methods and/or the inclusion of different patient cohorts, one may consider an alternative possibility, in light of the recent experimental data showing that the genetic background and/or coexisting biochemical defects can dictate whether STAT3 exert oncogenic or tumor suppressor effects in cancer cells

  • In addition to its dominant negative role, STAT3β is believed to carry other functions, considering the fact that it possesses most of the important STAT3 functional domains including the activation domain, the Src homology2 (SH2) domain that is responsible for STAT3 dimerization and its binding to the receptor complex (e.g., Janus kinases (JAKs)), the coiled-coil domain that allows STAT3 to interact with other proteins, and the DNA binding domain

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Summary

The Normal Functions of STAT3

STAT3 belongs to a family of transcription factors that transduces the cellular signals from a host of cytokines and soluble growth factors such as the IL-6 family cytokines, epidermal growth factor and platelet-derived growth factor [1,2]. The JAK-bound STAT3 molecules are phosphorylated by JAKs at the tyrosine residue. The phosphorylated STAT3 (pSTAT3) molecules form homodimers, which migrate to the nuclei where they bind to the promoters of various target genes and regulate their transcriptions [1,2]. In recent years, accumulating evidence has suggested the existence of the non-canonical pathway, in which the functions of STAT3 are independent of the phosphorylation of STAT3Y705 or its nuclear translocation [5]. STAT3 has important and diverse biological functions in normal cells, and details can be found in a number of excellent reviews [6,7,8]. Its biological importance is highlighted by the observation that STAT3 gene ablation in mice results in embryonic lethality that occurs 6–7 days after inception [9]. STAT3 was shown to be important in mediating the anti-apoptotic effect of IL-6 in the presence of a low-serum culture environment [13]

An Overview
Mechanisms Underlying the Constitutive Activation of STAT3 in Cancer
Loss of the Negative Regulation of STAT3
Excessive Stimulation of STAT3
Positive Feedback Loops that Sustain Persistent STAT3 Activation
Constitutively Active Somatic STAT3 Mutations
Canonical Mechanisms
Non-Canonical Mechanisms
STAT3 Can Exert Tumor Suppressor Effects
Mechanisms That Mediate or Regulate the Tumor Suppressor Function of STAT3
Clinical Observations Supporting the Tumor Suppressor Role of STAT3
STAT3β Has Biochemical and Biological Features Different from STAT3α
The Dominant Negative Role of STAT3β
STAT3β Regulates a Gene Set That Is Distinct from That of STAT3α
STAT3β Regulates the Phosphorylation Dynamics of STAT3α
Is STAT3β Responsible for the Tumor Suppressor Function of STAT3?
Evaluation of STAT3 Expression in Patient Samples
Conclusions

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