STAT3

Official Full Name

signal transducer and activator of transcription 3

Organism

Homo sapiens

GeneID

6774

Background

The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is activated through phosphorylation in response to various cytokines and growth factors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. This protein mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein is a specific inhibitor of this protein. This gene also plays a role in regulating host response to viral and bacterial infections. Mutations in this gene are associated with infantile-onset multisystem autoimmune disease and hyper-immunoglobulin E syndrome. [provided by RefSeq, Aug 2020]

Synonyms

APRF; HIES; ADMIO; ADMIO1;

Bio Chemical Class

Transcription factor

Protein Sequence

MAQWNQLQQLDTRYLEQLHQLYSDSFPMELRQFLAPWIESQDWAYAASKESHATLVFHNLLGEIDQQYSRFLQESNVLYQHNLRRIKQFLQSRYLEKPMEIARIVARCLWEESRLLQTAATAAQQGGQANHPTAAVVTEKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIVSELAGLLSAMEYVQKTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPIVQHRPMLEERIVELFRNLMKSAFVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESNNGSLSAEFKHLTLREQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWYNMLTNNPKNVNFFTKPPIGTWDQVAEVLSWQFSSTTKRGLSIEQLTTLAEKLLGPGVNYSGCQITWAKFCKENMAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSKEGGVTFTWVEKDISGKTQIQSVEPYTKQQLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYCRPESQEHPEADPGSAAPYLKTKFICVTPTTCSNTIDLPMSPRTLDSLMQFGNNGEGAEPSAGGQFESLTFDMELTSECATSPM

Open

Disease

Brain cancer, Colorectal cancer, Immune system disease, Liver cancer, Malignant digestive organ neoplasm, Malignant haematopoietic neoplasm, Mature B-cell leukaemia, Multiple myeloma, Mycosis fungoides, Pancreatic cancer, Postoperative inflammation, Psoriasis, Respiratory infection, Solid tumour/cancer, Ulcerative colitis

Approved Drug

1 +

Clinical Trial Drug

15 +

Discontinued Drug

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Detailed Information

Signal transducer and activator of transcription-3 (STAT3), also known as acute phase response factor (APRF), is a DNA-binding transcription factor. STAT3 belongs to the STAT family of transcription factors consisting of seven proteins, namely, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. The Janus kinase (JAK)–STAT pathway was originally discovered in the context of interferon-α (IFNα)-, IFNγ- and intereukin‑6 (IL‑6)-mediated downstream signaling. Of the seven members of the STAT protein family, STAT3 and STAT5 have been demonstrated to be the most important for cancer progression. They are not only crucial for transducing signals from numerous receptor and non-receptor tyrosine kinases that are frequently activated in cancer cells, but they are also transcription factors that regulate the expression of a wide range of genes, thereby contributing to tumor progression. Although both STAT3 and STAT5 contribute to tumor cell proliferation and survival, a notable feature of STAT3 as a promising target for cancer therapy is that it also has a crucial role in stromal cells, including immune cells, which are recruited to the tumor microenvironment to promote tumor progression. Importantly, STAT3 activation also functions as a potent immune checkpoint for multiple antitumor immune responses.

Figure 1. Pathways activating JAK–STAT3 signaling in cancer.

Role of STAT3 in tumorigenesis

Among the earliest clues that STATs contribute to oncogenesis were the findings that STAT3 is constitutively activated in Src-transformed cell lines and that interrupting STAT3 signaling blocks the transformation of mouse fibroblasts by the Src oncoprotein. The first direct links between STATs and human cancer came from the findings that constitutive STAT3 activity is required for the growth of head and neck cancer cells and of multiple-myeloma cells. In contrast to the transient nature of STAT3 activation in normal cells, persistent activation of STAT3 has been reported in a variety of human tumor cell lines and primary human tumors, including leukemias, lymphomas, multiple myeloma, glioma, melanoma, head and neck, breast, ovarian, endometrial, cervical, colon, pancreatic, lung, brain, renal, and prostate cancers. This increased level of phosphorylated STAT3 is not due to mutations in STAT3 but arises from oversupply of growth factors, such as TGFα or (IL6-family) cytokines within the tumor microenvironment that activate STAT3 in a paracrine manner.

The activation of oncogenes, inactivation of tumor-suppressor genes, chromosomal rearrangement/amplification, deregulation of multiple potential upstream inputs such as elevated EGFR expression levels, EGFR mutations that result in constitutive RTK activation, over-expression of Src or other SFKs, mutations that hyperactivate JAKs and other genetic events in neoplastic cells directly trigger STAT3 activation or the release of inflammatory mediators as part of an autocrine pathway. Hyper-activation of STAT3 can also result from impairment mutations in any of the negative regulatory proteins, which limit the extent of STAT3 activation in normal cells. For example, epigenetic silencing of SOCS3 by hypermethylation in CpG islands of the functional SOCS-3 promoter in human lung cancers as well as mutations in STAT3-inactivating receptor protein tyrosine phosphatase delta in glioblastoma and other human cancers leads to STAT3-mediated cell proliferation and survival.

STAT3 and inflammation, obesity, diabetes, as well as cancer

A crucial role of JAK–STAT3 in cancer inflammation has been well documented. One recent study demonstrated that IL‑6–JAK2–STAT3 signaling in the liver exacerbates metabolic stress-induced inflammation in obese mice, accelerating the incidence of HCC18. Increased IL‑6 in the hepatic microenvironment upregulates STAT3 activity through JAK2 activation, which is required for the development of the malignant hepatic phenotype. Blocking IL‑6 in diet-induced obese mice or treating obese mice with the JAK2 inhibitor AG490 suppresses hepatic inflammation as well as tumor growth through STAT3 inhibition. IL‑6–STAT3 signaling in colon epithelial cells is also important for the development of obesity-associated colon cancer. These results suggest that activation of the JAK–STAT3 pathway in epithelial cells can promote the development of obesity-associated cancer through the activation of inflammatory immune responses.

STAT3 activity in T cells promotes obesity as well as insulin resistance. In HFD-fed mice, blocking STAT3 signaling in T cells decreases local adipose tissue inflammation, reducing obesity and insulin resistance, further demonstrating that STAT3 is a molecular nexus between inflammation and obesity. This study also illustrates a link between type 2 diabetes and STAT3 activation, which indirectly suggests that type 2 diabetes could enhance cancer development via STAT3 signaling. Supporting this hypothesis are recent findings with metformin, a front-line drug for treating type 2 diabetes. Metformin lowers the risk of cancer incidence in patients with diabetes, and treatment of triple negative breast cancer (TNBC) cells with metformin selectively target STAT3 and induce apoptosis. Furthermore, the use of metformin together with STAT3 inhibitors synergistically increases TNBC apoptosis, raising the possibility of combination treatment with STAT3 inhibitors and metformin to augment therapeutic efficacy in TNBCs.

References:

Yu H, et al. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nature Reviews Cancer, 2014, 14(11):736-746.
Siveen K S, et al. Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2014, 1845(2):136-154.
Carpenter R, Lo H W. STAT3 Target Genes Relevant to Human Cancers. Cancers, 2014, 6(2):897-925.

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