Role of STAT3 in cancer metastasis and translational advances

Mohammad Zahid Kamran, Prachi Patil, Rajiv P Gude, Mohammad Zahid Kamran, Prachi Patil, Rajiv P Gude

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis. In this paper, we first describe the mechanism of STAT3 regulation followed by how STAT3 is involved in cancer metastasis, then we summarize the various small molecule inhibitors that inhibit STAT3 signaling.

Figures

Figure 1
Figure 1
Binding of various ligands to their cognate cell surface receptors, results in phosphorylation of STAT3 molecules that further dimerizes with each other at SH2 domain and gets translocated to the nucleus. Following translocation, the dimerized STAT3 molecule binds to the promoter of target genes and activates their transcription. STAT3 regulate Cyclin D1, cMyc, BclXL, Mcl1 and p53, thereby regulating cellular proliferation and survival. STAT3 directly binds to the promoter of MMP2 and upregulates its expression. Additionally, STAT3 also regulate activity of MMP9 and MMP7. STAT3 regulates cellular migration by modulating the activity of Rho and Rac. Angiogenesis required for tumor growth and metastasis. STAT3 is seen to be regulating angiogenesis by upregulating the activity of VEGF and HIFα.

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Source: PubMed

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