Signal transducer and activator of transcription 3 (STAT3) is atranscription factor which in humans is encoded by theSTAT3gene.[5] It is a member of theSTAT protein family.
STAT3-deficient mouseembryos cannot develop beyond embryonic day 7, when gastrulation begins.[10] It appears that at these early stages of development, STAT3 activation is required for self-renewal ofembryonic stem cells (ESCs). Indeed,LIF, which is supplied tomurine ESC cultures to maintain theirundifferentiated state, can be omitted if STAT3 is activated through some other means.[11]
STAT3 is essential for the differentiation of theTH17 helper T cells, which have been implicated in a variety ofautoimmune diseases.[12] During viral infection, mice lacking STAT3 in T-cells display impairment in the ability to generate T-follicular helper (Tfh) cells and fail to maintain antibody based immunity.[13]
STAT3 caused upregulation in E-selectin, a factor in metastasis of cancers.[14]
Hyperactivation of STAT3 occurs inCOVID-19 infection and other viral infections.[15][16]
Loss-of-function mutations in the STAT3 gene result inhyperimmunoglobulin E syndrome, associated with recurrent infections as well as disordered bone and tooth development.[17]
Gain-of-function mutations in the STAT3 gene have been reported to cause multi-organ early onset auto-immune diseases; such as thyroid disease, diabetes, intestinal inflammation, and low blood counts,[18] while constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.[19][20][21][22] It has anti-apoptotic as well as proliferative effects.[19]
STAT3 can promote oncogenesis by being constitutively active through various pathways as mentioned elsewhere. A tumor suppressor role of STAT3 has also been reported.[23][24][25] In the report on humanglioblastoma tumor, or brain cancer, STAT3 was shown to have an oncogenic or a tumor suppressor role depending upon the mutational background of the tumor. A direct connection between the PTEN-Akt-FOXO axis (suppressive) and the leukemia inhibitory factor receptor beta (LIFRbeta)-STAT3 signaling pathway (oncogenic) was shown. Overactivation of STAT3 promotes tumor survival and reduces sensitivity to temozolomide (TMZ), the standard chemotherapy for this cancer. Systemic inhibition of STAT3, however, risks immune dysregulation, complicating its therapeutic targeting. Recent studies highlight a non-coding RNA transcribed from a STAT3 enhancer region, termed TMZR1-eRNA, which regulates STAT3 expression. Silencing TMZR1-eRNA reduces STAT3 mRNA and protein levels, sensitizing glioblastoma cells to TMZ-induced cell death. Mechanistically, TMZR1-eRNA enhances STAT3 promoter activity, creating a feedback loop that sustains STAT3 expression. Importantly, TMZR1-eRNA expression is minimal in healthy brain tissue and peripheral blood cells, suggesting its suppression could offer a tumor-specific strategy to overcome chemoresistance with reduced off-target effects compared to direct STAT3 inhibitors[26]
Increased activity of STAT3 in cancer cells, leads to changes in the function of protein complexes that control expression of inflammatory genes, with result profound change in the secretome and the cell phenotypes, their activity in the tumor, and their capacity for metastasis.[27]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, et al. (April 1994). "Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway".Cell.77 (1):63–71.doi:10.1016/0092-8674(94)90235-6.PMID7512451.S2CID42211976.
^Lim CP, Cao X (November 2006). "Structure, function, and regulation of STAT proteins".Molecular BioSystems.2 (11):536–50.doi:10.1039/B606246F.PMID17216035..
^Levy DE, Loomis CA (October 2007). "STAT3 signaling and the hyper-IgE syndrome".The New England Journal of Medicine.357 (16):1655–8.doi:10.1056/NEJMe078197.PMID17881746.
^Stasevich EM (April 2025). "Enhancer RNA from STAT3 locus affects temozolomide chemoresistance of glioblastoma cells".Gene.944 149297.doi:10.1016/j.gene.2025.149297.PMID39889913.
^Matsuda T, Junicho A, Yamamoto T, Kishi H, Korkmaz K, Saatcioglu F, et al. (April 2001). "Cross-talk between signal transducer and activator of transcription 3 and androgen receptor signaling in prostate carcinoma cells".Biochemical and Biophysical Research Communications.283 (1):179–87.Bibcode:2001BBRC..283..179M.doi:10.1006/bbrc.2001.4758.PMID11322786.
^Sanchez-Margalet V, Martin-Romero C (July 2001). "Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway".Cellular Immunology.211 (1):30–6.doi:10.1006/cimm.2001.1815.PMID11585385.
^Hwang JH, Kim DW, Suh JM, Kim H, Song JH, Hwang ES, et al. (June 2003). "Activation of signal transducer and activator of transcription 3 by oncogenic RET/PTC (rearranged in transformation/papillary thyroid carcinoma) tyrosine kinase: roles in specific gene regulation and cellular transformation".Molecular Endocrinology.17 (6):1155–66.doi:10.1210/me.2002-0401.PMID12637586.
^Kim J, Kim D, Chung J (2000). "Replication protein a 32 kDa subunit (RPA p32) binds the SH2 domain of STAT3 and regulates its transcriptional activity".Cell Biology International.24 (7):467–73.doi:10.1006/cbir.2000.0525.PMID10875894.S2CID23783745.
Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW (February 2002). "Signaling through the JAK/STAT pathway, recent advances and future challenges".Gene.285 (1–2):1–24.doi:10.1016/S0378-1119(02)00398-0.PMID12039028.
Joseph AM, Kumar M, Mitra D (January 2005). "Nef: "necessary and enforcing factor" in HIV infection".Current HIV Research.3 (1):87–94.doi:10.2174/1570162052773013.PMID15638726.
Leeman RJ, Lui VW, Grandis JR (March 2006). "STAT3 as a therapeutic target in head and neck cancer".Expert Opinion on Biological Therapy.6 (3):231–41.doi:10.1517/14712598.6.3.231.PMID16503733.S2CID3092794.
Aggarwal BB, Sethi G, Ahn KS, Sandur SK, Pandey MK, Kunnumakkara AB, et al. (December 2006). "Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution".Annals of the New York Academy of Sciences.1091 (1):151–69.Bibcode:2006NYASA1091..151A.doi:10.1196/annals.1378.063.PMID17341611.S2CID814675.
Yu H, Kortylewski M, Pardoll D (January 2007). "Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment".Nature Reviews Immunology.7 (1):41–51.doi:10.1038/nri1995.PMID17186030.S2CID20191132.
