Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor with many important functions in the biology of normal and transformed cells. Its regulation is highly complex as it is involved in signaling pathways in many different cell types and under a wide variety of conditions. Besides other functions, STAT3 is an important regulator of normal stem cells and cancer stem cells. p63 which is a member of the p53 protein family is also involved in these functions and is both physically and functionally connected with STAT3. This review summarizes STAT3 function and regulation, its role in stem cell and cancer stem cell properties and highlights recent reports about its relationship to p63.

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Nylander K, Vojtesek B, Nenutil R, Lindgren B, Roos G, Zhanxiang W, et al. Differential expression of p63 isoforms in normal tissues and neoplastic cells. J Pathol. 2002;198:417–427. PubMed

Nekulova M, Holcakova J, Nenutil R, Stratmann R, Bouchalova P, Müller P, et al. Characterization of specific p63 and p63-N-terminal isoform antibodies and their application for immunohistochemistry. Virchows Arch. 2013;463:415–425. PubMed

Orzol P, Nekulova M, Holcakova J, Muller P, Votesek B, Coates PJ. ΔNp63 regulates cell proliferation, differentiation, adhesion, and migration in the BL2 subtype of basal-like breast cancer. Tumour Biol. 2016;37:10133–10140. PubMed

Holcakova J, Nekulova M, Orzol P, Nenutil R, Podhorec J, Svoboda M, et al. ΔNp63 activates EGFR signaling to induce loss of adhesion in triple-negative basal-like breast cancer cells. Breast Cancer Res Treat. 2017;163:475–484. PubMed

Banerjee K, Resat H. Constitutive activation of STAT3 in breast cancer cells: A review. Int J Cancer. 2016;138:2570–2578. PubMed PMC

Carpenter RL, Lo HW. STAT3 Target Genes Relevant to Human Cancers. Cancers (Basel). 2014;6:897–925. PubMed PMC

Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9:798–809. PubMed PMC

Nekulova M, Holcakova J, Coates P, Vojtesek B. The role of p63 in cancer, stem cells and cancer stem cells. Cell Mol Biol Lett. 2011;16:296–327. PubMed PMC

Orzol P, Holcakova J, Nekulova M, Nenutil R, Vojtesek B, Coates PJ. The diverse oncogenic and tumour suppressor roles of p63 and p73 in cancer: a review by cancer site. Histol Histopathol. 2015;30:503–521. PubMed

Avalle L, Camporeale A, Camperi A, Poli V. STAT3 in cancer: A double edged sword. Cytokine. 2017;98:42–50. PubMed

Bishop JA, Teruya-Feldstein J, Westra WH, Pelosi G, Travis WD, Rekhtman N. p40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol. 2012;25:405–415. PubMed

Pellegrini G, Dellambra E, Golisano O, Martinelli E, Fantozzi I, Bondanza S, et al. p63 identifies keratinocyte stem cells. Proc Natl Acad Sci U S A. 2001;98:3156–3161. PubMed PMC

Memmi EM, Sanarico AG, Giacobbe A, Peschiaroli A, Frezza V, Cicalese A, et al. p63 Sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling. Proc Natl Acad Sci U S A. 2015;112:3499–3504. PubMed PMC

You L, Wang Z, Li H, Shou J, Jing Z, Xie J, et al. The role of STAT3 in autophagy. Autophagy. 2015;11:729–739. PubMed PMC

Caldenhoven E, van Dijk TB, Solari R, Armstrong J, Raaijmakers JA, Lammers JW, et al. STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription. J Biol Chem. 1996;271:13221–13227. PubMed

The UniProt Consortium UniProt: the universal protein knowledgebase. Nucleic Acids Res. 2017;45:D158–DD69. PubMed PMC

Schaefer TS, Sanders LK, Nathans D. Cooperative transcriptional activity of Jun and Stat3 beta, a short form of Stat3. Proc Natl Acad Sci U S A. 1995;92:9097–9101. PubMed PMC

Maritano D, Sugrue ML, Tininini S, Dewilde S, Strobl B, Fu X, et al. The STAT3 isoforms alpha and beta have unique and specific functions. Nat Immunol. 2004;5:401–409. PubMed

Kato T, Sakamoto E, Kutsuna H, Kimura-Eto A, Hato F, Kitagawa S. Proteolytic conversion of STAT3alpha to STAT3gamma in human neutrophils: role of granule-derived serine proteases. J Biol Chem. 2004;279:31076–31080. PubMed

Hevehan DL, Miller WM, Papoutsakis ET. Differential expression and phosphorylation of distinct STAT3 proteins during granulocytic differentiation. Blood. 2002;99:1627–1637. PubMed

Nishiki S, Hato F, Kamata N, Sakamoto E, Hasegawa T, Kimura-Eto A, et al. Selective activation of STAT3 in human monocytes stimulated by G-CSF: implication in inhibition of LPS-induced TNF-alpha production. Am J Physiol Cell Physiol. 2004;286:C1302–C1311. PubMed

Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, et al. Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nat Biotechnol. 2005;23:94–101. PubMed

Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, et al. An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014;96:253–262. PubMed

Levy DE, Darnell JE. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3:651–662. PubMed

Fagard R, Metelev V, Souissi I, Baran-Marszak F. STAT3 inhibitors for cancer therapy: Have all roads been explored? JAKSTAT. 2013;2:e22882. PubMed PMC

Zhong Z, Wen Z, Darnell JE. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994;264:95–98. PubMed

Darnell JE, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264:1415–1421. PubMed

Decker T, Kovarik P, Meinke A. GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. J Interferon Cytokine Res. 1997;17:121–134. PubMed

Khan A, Fornes O, Stigliani A, Gheorghe M, Castro-Mondragon JA, van der Lee R, et al. JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework. Nucleic Acids Res. 2017; PubMed PMC

Khatib H, Huang W, Mikheil D, Schutzkus V, Monson RL. Effects of signal transducer and activator of transcription (STAT) genes STAT1 and STAT3 genotypic combinations on fertilization and embryonic survival rates in Holstein cattle. J Dairy Sci. 2009;92:6186–6191. PubMed

Decker T, Kovarik P. Transcription factor activity of STAT proteins: structural requirements and regulation by phosphorylation and interacting proteins. Cell Mol Life Sci. 1999;55:1535–1546. PubMed PMC

Gupta M, Han JJ, Stenson M, Maurer M, Wellik L, Hu G, et al. Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation. Blood. 2012;119:2844–2853. PubMed PMC

Ernst M, Najdovska M, Grail D, Lundgren-May T, Buchert M, Tye H, et al. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J Clin Invest. 2008;118:1727–1738. PubMed PMC

Peterson WM, Wang Q, Tzekova R, Wiegand SJ. Ciliary neurotrophic factor and stress stimuli activate the Jak-STAT pathway in retinal neurons and glia. J Neurosci. 2000;20:4081–4090. PubMed PMC

Kunisada K, Hirota H, Fujio Y, Matsui H, Tani Y, Yamauchi-Takihara K, et al. Activation of JAK-STAT and MAP kinases by leukemia inhibitory factor through gp130 in cardiac myocytes. Circulation. 1996;94:2626–2632. PubMed

Yanagisawa M, Nakashima K, Taga T. STAT3-mediated astrocyte differentiation from mouse fetal neuroepithelial cells by mouse oncostatin M. Neurosci Lett. 1999;269:169–172. PubMed

Wang Y, van Boxel-Dezaire AH, Cheon H, Yang J, Stark GR. STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proc Natl Acad Sci U S A. 2013;110:16975–16980. PubMed PMC

Zhao D, Pan C, Sun J, Gilbert C, Drews-Elger K, Azzam DJ, et al. VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2. Oncogene. 2015;34:3107–3119. PubMed

Vignais ML, Sadowski HB, Watling D, Rogers NC, Gilman M. Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins. Mol Cell Biol. 1996;16:1759–1769. PubMed PMC

Zong CS, Chan J, Levy DE, Horvath C, Sadowski HB, Wang LH. Mechanism of STAT3 activation by insulin-like growth factor I receptor. J Biol Chem. 2000;275:15099–15105. PubMed

Schreiner SJ, Schiavone AP, Smithgall TE. Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. J Biol Chem. 2002;277:45680–45687. PubMed

Coppo P, Flamant S, De Mas V, Jarrier P, Guillier M, Bonnet ML, et al. BCR-ABL activates STAT3 via JAK and MEK pathways in human cells. Br J Haematol. 2006;134:171–179. PubMed

Guryanova OA, Wu Q, Cheng L, Lathia JD, Huang Z, Yang J, et al. Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3. Cancer Cell. 2011;19:498–511. PubMed PMC

Kortylewski M, Kujawski M, Herrmann A, Yang C, Wang L, Liu Y, et al. Toll-like receptor 9 activation of signal transducer and activator of transcription 3 constrains its agonist-based immunotherapy. Cancer Res. 2009;69:2497–2505. PubMed PMC

Eyking A, Ey B, Rünzi M, Roig AI, Reis H, Schmid KW, et al. Toll-like receptor 4 variant D299G induces features of neoplastic progression in Caco-2 intestinal cells and is associated with advanced human colon cancer. Gastroenterology. 2011;141:2154–2165. PubMed PMC

Lee H, Deng J, Kujawski M, Yang C, Liu Y, Herrmann A, et al. STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nat Med. 2010;16:1421–1428. PubMed PMC

Lee JL, Wang MJ, Chen JY. Acetylation and activation of STAT3 mediated by nuclear translocation of CD44. J Cell Biol. 2009;185:949–957. PubMed PMC

Zheng L, Jia X, Zhang C, Wang D, Cao Z, Wang J, et al. Angiotensin II in atrial structural remodeling: the role of Ang II/JAK/STAT3 signaling pathway. Am J Transl Res. 2015;7:1021–1031. PubMed PMC

Geletu M, Arulanandam R, Chevalier S, Saez B, Larue L, Feracci H, et al. Classical cadherins control survival through the gp130/Stat3 axis. Biochim Biophys Acta. 2013;1833:1947–1959. PubMed

Turkson J, Bowman T, Adnane J, Zhang Y, Djeu JY, Sekharam M, et al. Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein. Mol Cell Biol. 1999;19:7519–7528. PubMed PMC

Chung J, Uchida E, Grammer TC, Blenis J. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol. 1997;17:6508–6516. PubMed PMC

Lim CP, Cao X. Serine phosphorylation and negative regulation of Stat3 by JNK. J Biol Chem. 1999;274:31055–31061. PubMed

Jain N, Zhang T, Kee WH, Li W, Cao X. Protein kinase C delta associates with and phosphorylates Stat3 in an interleukin-6-dependent manner. J Biol Chem. 1999;274:24392–24400. PubMed

Kim JH, Yoon MS, Chen J. Signal transducer and activator of transcription 3 (STAT3) mediates amino acid inhibition of insulin signaling through serine 727 phosphorylation. J Biol Chem. 2009;284:35425–35432. PubMed PMC

Wen Z, Zhong Z, Darnell JE. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995;82:241–250. PubMed

Zhang X, Blenis J, Li HC, Schindler C, Chen-Kiang S. Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science. 1995;267:1990–1994. PubMed

Shi X, Zhang H, Paddon H, Lee G, Cao X, Pelech S. Phosphorylation of STAT3 serine-727 by cyclin-dependent kinase 1 is critical for nocodazole-induced mitotic arrest. Biochemistry. 2006;45:5857–5867. PubMed

Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006;442:823–826. PubMed

Liu H, Ma Y, Cole SM, Zander C, Chen KH, Karras J, et al. Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival. Blood. 2003;102:344–352. PubMed

Qin HR, Kim HJ, Kim JY, Hurt EM, Klarmann GJ, Kawasaki BT, et al. Activation of signal transducer and activator of transcription 3 through a phosphomimetic serine 727 promotes prostate tumorigenesis independent of tyrosine 705 phosphorylation. Cancer Res. 2008;68:7736–7741. PubMed PMC

Frank DA, Mahajan S, Ritz J. B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. J Clin Invest. 1997;100:3140–3148. PubMed PMC

Hazan-Halevy I, Harris D, Liu Z, Liu J, Li P, Chen X, et al. STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood. 2010;115:2852–2863. PubMed PMC

Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, et al. Function of mitochondrial Stat3 in cellular respiration. Science. 2009;323:793–797. PubMed PMC

Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science. 2009;324:1713–1716. PubMed PMC

Liu L, McBride KM, Reich NC. STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3. Proc Natl Acad Sci U S A. 2005;102:8150–8155. PubMed PMC

Cimica V, Chen HC, Iyer JK, Reich NC. Dynamics of the STAT3 transcription factor: nuclear import dependent on Ran and importin-β1. PLoS One. 2011;6:e20188. PubMed PMC

Butturini E, Gotte G, Dell'Orco D, Chiavegato G, Marino V, Canetti D, et al. Intermolecular disulfide bond influences unphosphorylated STAT3 dimerization and function. Biochem J. 2016;473(19):3205. PubMed

Timofeeva OA, Chasovskikh S, Lonskaya I, Tarasova NI, Khavrutskii L, Tarasov SG, et al. Mechanisms of unphosphorylated STAT3 transcription factor binding to DNA. J Biol Chem. 2012;287:14192–14200. PubMed PMC

Nkansah E, Shah R, Collie GW, Parkinson GN, Palmer J, Rahman KM, et al. Observation of unphosphorylated STAT3 core protein binding to target dsDNA by PEMSA and X-ray crystallography. FEBS Lett. 2013;587:833–839. PubMed

Yang J, Chatterjee-Kishore M, Staugaitis SM, Nguyen H, Schlessinger K, Levy DE, et al. Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res. 2005;65:939–947. PubMed

Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev. 2007;21:1396–1408. PubMed PMC

Yuan ZL, Guan YJ, Chatterjee D, Chin YE. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science. 2005;307:269–273. PubMed

Wang R, Cherukuri P, Luo J. Activation of Stat3 sequence-specific DNA binding and transcription by p300/CREB-binding protein-mediated acetylation. J Biol Chem. 2005;280:11528–11534. PubMed

Dasgupta M, Unal H, Willard B, Yang J, Karnik SS, Stark GR. Critical role for lysine 685 in gene expression mediated by transcription factor unphosphorylated STAT3. J Biol Chem. 2014;289:30763–30771. PubMed PMC

Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell. 2013;23:839–852. PubMed PMC

Su F, Ren F, Rong Y, Wang Y, Geng Y, Feng M, et al. Protein tyrosine phosphatase Meg2 dephosphorylates signal transducer and activator of transcription 3 and suppresses tumor growth in breast cancer. Breast Cancer Res. 2012;14:R38. PubMed PMC

Kumar V, Cheng P, Condamine T, Mony S, Languino LR, McCaffrey JC, et al. CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation. Immunity. 2016;44:303–315. PubMed PMC

Kim DJ, Tremblay ML, Digiovanni J. Protein tyrosine phosphatases, TC-PTP, SHP1, and SHP2, cooperate in rapid dephosphorylation of Stat3 in keratinocytes following UVB irradiation. PLoS One. 2010;5:e10290. PubMed PMC

Zgheib C, Zouein FA, Chidiac R, Kurdi M, Booz GW. Calyculin A reveals serine/threonine phosphatase protein phosphatase 1 as a regulatory nodal point in canonical signal transducer and activator of transcription 3 signaling of human microvascular endothelial cells. J Interferon Cytokine Res. 2012;32:87–94. PubMed PMC

Lu D, Liu L, Ji X, Gao Y, Chen X, Liu Y, et al. The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation. Nat Immunol. 2015;16:1263–1273. PubMed

Yuan J, Zhang F, Niu R. Multiple regulation pathways and pivotal biological functions of STAT3 in cancer. Sci Rep. 2015;5:17663. PubMed PMC

Nicholson SE, De Souza D, Fabri LJ, Corbin J, Willson TA, Zhang JG, et al. Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci U S A. 2000;97:6493–6498. PubMed PMC

Lee JH, Kim C, Sethi G, Ahn KS. Brassinin inhibits STAT3 signaling pathway through modulation of PIAS-3 and SOCS-3 expression and sensitizes human lung cancer xenograft in nude mice to paclitaxel. Oncotarget. 2015;6:6386–6405. PubMed PMC

Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, et al. Specific inhibition of Stat3 signal transduction by PIAS3. Science. 1997;278:1803–1805. PubMed

Yang J, Huang J, Dasgupta M, Sears N, Miyagi M, Wang B, et al. Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc Natl Acad Sci U S A. 2010;107:21499–21504. PubMed PMC

Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014;14:736–746. PubMed

Cai B, Li J, Wang J, Luo X, Ai J, Liu Y, et al. microRNA-124 regulates cardiomyocyte differentiation of bone marrow-derived mesenchymal stem cells via targeting STAT3 signaling. Stem Cells. 2012;30:1746–1755. PubMed

Jiang J, Li Z, Yu C, Chen M, Tian S, Sun C. MiR-1181 inhibits stem cell-like phenotypes and suppresses SOX2 and STAT3 in human pancreatic cancer. Cancer Lett. 2015;356:962–970. PubMed

Zhang H, Cai K, Wang J, Wang X, Cheng K, Shi F, et al. MiR-7, inhibited indirectly by lincRNA HOTAIR, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway. Stem Cells. 2014;32:2858–2868. PubMed

Pawlus MR, Wang L, Hu CJ. STAT3 and HIF1α cooperatively activate HIF1 target genes in MDA-MB-231 and RCC4 cells. Oncogene. 2014;33:1670–1679. PubMed PMC

Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–111. PubMed

Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–676. PubMed

Humphrey RK, Beattie GM, Lopez AD, Bucay N, King CC, Firpo MT, et al. Maintenance of pluripotency in human embryonic stem cells is STAT3 independent. Stem Cells. 2004;22:522–530. PubMed

Davis S, Aldrich TH, Stahl N, Pan L, Taga T, Kishimoto T, et al. LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science. 1993;260:1805–1808. PubMed

Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T, et al. STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO J. 1999;18:4261–4269. PubMed PMC

Raz R, Lee CK, Cannizzaro LA, d'Eustachio P, Levy DE. Essential role of STAT3 for embryonic stem cell pluripotency. Proc Natl Acad Sci U S A. 1999;96:2846–2851. PubMed PMC

Cartwright P, McLean C, Sheppard A, Rivett D, Jones K, Dalton S. LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development. 2005;132:885–896. PubMed

Chen CY, Lee DS, Yan YT, Shen CN, Hwang SM, Lee ST, et al. Bcl3 Bridges LIF-STAT3 to Oct4 Signaling in the Maintenance of Naïve Pluripotency. Stem Cells. 2015;33:3468–3480. PubMed

Torres J, Watt FM. Nanog maintains pluripotency of mouse embryonic stem cells by inhibiting NFkappaB and cooperating with Stat3. Nat Cell Biol. 2008;10:194–201. PubMed

Huang G, Yan H, Ye S, Tong C, Ying QL. STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates mouse ESC fates. Stem Cells. 2014;32:1149–1160. PubMed PMC

Gu F, Hata R, Ma YJ, Tanaka J, Mitsuda N, Kumon Y, et al. Suppression of Stat3 promotes neurogenesis in cultured neural stem cells. J Neurosci Res. 2005;81:163–171. PubMed

Kamakura S, Oishi K, Yoshimatsu T, Nakafuku M, Masuyama N, Gotoh Y. Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling. Nat Cell Biol. 2004;6:547–554. PubMed

Yoshimatsu T, Kawaguchi D, Oishi K, Takeda K, Akira S, Masuyama N, et al. Non-cell-autonomous action of STAT3 in maintenance of neural precursor cells in the mouse neocortex. Development. 2006;133:2553–2563. PubMed

Chung YJ, Park BB, Kang YJ, Kim TM, Eaves CJ, Oh IH. Unique effects of Stat3 on the early phase of hematopoietic stem cell regeneration. Blood. 2006;108:1208–1215. PubMed

Zhu H, Xiao F, Wang G, Wei X, Jiang L, Chen Y, et al. STAT3 Regulates Self-Renewal of Adult Muscle Satellite Cells during Injury-Induced Muscle Regeneration. Cell Rep. 2016;16:2102–2115. PubMed

Tadokoro T, Wang Y, Barak LS, Bai Y, Randell SH, Hogan BL. IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells. Proc Natl Acad Sci U S A. 2014;111:E3641–E3649. PubMed PMC

Yuan Y, Xi Y, Chen J, Zhu P, Kang J, Zou Z, et al. STAT3 stimulates adipogenic stem cell proliferation and cooperates with HMGA2 during the early stage of differentiation to promote adipogenesis. Biochem Biophys Res Commun. 2017;482:1360–1366. PubMed

Chen Q, Quan Y, Wang N, Xie C, Ji Z, He H, et al. Inactivation of STAT3 Signaling Impairs Hair Cell Differentiation in the Developing Mouse Cochlea. Stem Cell Reports. 2017;9:231–246. PubMed PMC

Staniszewska AD, Pensa S, Caffarel MM, Anderson LH, Poli V, Watson CJ. Stat3 is required to maintain the full differentiation potential of mammary stem cells and the proliferative potential of mammary luminal progenitors. PLoS One. 2012;7:e52608. PubMed PMC

Dahéron L, Opitz SL, Zaehres H, Lensch MW, Lensch WM, Andrews PW, et al. LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells. 2004;22:770–778. PubMed

Yang J, van Oosten AL, Theunissen TW, Guo G, Silva JC, Smith A. Stat3 activation is limiting for reprogramming to ground state pluripotency. Cell Stem Cell. 2010;7:319–328. PubMed PMC

Chen H, Aksoy I, Gonnot F, Osteil P, Aubry M, Hamela C, et al. Reinforcement of STAT3 activity reprogrammes human embryonic stem cells to naive-like pluripotency. Nat Commun. 2015;6:7095. PubMed PMC

Matsui F, Babitz SA, Rhee A, Hile KL, Zhang H, Meldrum KK. Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production. Am J Physiol Renal Physiol. 2017;312:F25–F32. PubMed PMC

Hsu HS, Lin JH, Hsu TW, Su K, Wang CW, Yang KY, et al. Mesenchymal stem cells enhance lung cancer initiation through activation of IL-6/JAK2/STAT3 pathway. Lung Cancer. 2012;75:167–177. PubMed

Rattigan Y, Hsu JM, Mishra PJ, Glod J, Banerjee D. Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu. Exp Cell Res. 2010;316:3417–3424. PubMed

Buettner R, Mora LB, Jove R, Activated STAT. signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 2002;8:945–954. PubMed

Marotta LL, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, et al. The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24- stem cell-like breast cancer cells in human tumors. J Clin Invest. 2011;121:2723–2735. PubMed PMC

Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, et al. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res. 2017;45:D777–DD83. PubMed PMC

Xiong H, Du W, Wang JL, Wang YC, Tang JT, Hong J, et al. Constitutive activation of STAT3 is predictive of poor prognosis in human gastric cancer. J Mol Med (Berl). 2012;90:1037–1046. PubMed

Mora LB, Buettner R, Seigne J, Diaz J, Ahmad N, Garcia R, et al. Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res. 2002;62:6659–6666. PubMed

Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y, Azuma K, et al. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res. 2002;62:3351–3355. PubMed

Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123:725–731. PubMed

Lánczky A, Nagy Á, Bottai G, Munkácsy G, Szabó A, Santarpia L, et al. miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients. Breast Cancer Res Treat. 2016;160:439–446. PubMed

Rosen JM, Jordan CT. The increasing complexity of the cancer stem cell paradigm. Science. 2009;324:1670–1673. PubMed PMC

Korkaya H, Liu S, Wicha MS. Regulation of cancer stem cells by cytokine networks: attacking cancer's inflammatory roots. Clin Cancer Res. 2011;17:6125–6129. PubMed PMC

Badve S, Nakshatri H. Breast-cancer stem cells-beyond semantics. Lancet Oncol. 2012;13:e43–e48. PubMed

Pattabiraman DR, Weinberg RA. Tackling the cancer stem cells - what challenges do they pose? Nat Rev Drug Discov. 2014;13:497–512. PubMed PMC

Nassar D, Blanpain C. Cancer Stem Cells: Basic Concepts and Therapeutic Implications. Annu Rev Pathol. 2016;11:47–76. PubMed

Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–1948. PubMed

Lin L, Fuchs J, Li C, Olson V, Bekaii-Saab T, Lin J. STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH+/CD133+ stem cell-like human colon cancer cells. Biochem Biophys Res Commun. 2011;416:246–251. PubMed

Schroeder A, Herrmann A, Cherryholmes G, Kowolik C, Buettner R, Pal S, et al. Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Res. 2014;74:1227–1237. PubMed PMC

Su YJ, Lai HM, Chang YW, Chen GY, Lee JL. Direct reprogramming of stem cell properties in colon cancer cells by CD44. EMBO J. 2011;30:3186–3199. PubMed PMC

Chung SS, Aroh C, Vadgama JV. Constitutive activation of STAT3 signaling regulates hTERT and promotes stem cell-like traits in human breast cancer cells. PLoS One. 2013;8:e83971. PubMed PMC

Won C, Kim BH, Yi EH, Choi KJ, Kim EK, Jeong JM, et al. Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma. Hepatology. 2015;62:1160–1173. PubMed PMC

Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15:1010–1012. PubMed

Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29:4741–4751. PubMed PMC

Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–715. PubMed PMC

Morel AP, Lièvre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One. 2008;3:e2888. PubMed PMC

Wang SS, Jiang J, Liang XH, Tang YL. Links between cancer stem cells and epithelial-mesenchymal transition. Onco Targets Ther. 2015;8:2973–2980. PubMed PMC

Vazquez-Santillan K, Melendez-Zajgla J, Jimenez-Hernandez L, Martínez-Ruiz G, Maldonado V. NF-κB signaling in cancer stem cells: a promising therapeutic target? Cell Oncol (Dordr). 2015;38:327–339. PubMed

Tang Y, Kitisin K, Jogunoori W, Li C, Deng CX, Mueller SC, et al. Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling. Proc Natl Acad Sci U S A. 2008;105:2445–2450. PubMed PMC

Gujral TS, Chan M, Peshkin L, Sorger PK, Kirschner MW, MacBeath G. A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell. 2014;159:844–856. PubMed PMC

Peñuelas S, Anido J, Prieto-Sánchez RM, Folch G, Barba I, Cuartas I, et al. TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell. 2009;15:315–327. PubMed

Liu WH, Chen MT, Wang ML, Lee YY, Chiou GY, Chien CS, et al. Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid tumor cells. Oncotarget. 2015;6:1750–1768. PubMed PMC

Chung SS, Giehl N, Wu Y, Vadgama JV. STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits. Int J Oncol. 2014;44:403–411. PubMed PMC

Korkaya H, Kim GI, Davis A, Malik F, Henry NL, Ithimakin S, et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell. 2012;47:570–584. PubMed PMC

Aghazadeh S, Yazdanparast R. Activation of STAT3/HIF-1α/Hes-1 axis promotes trastuzumab resistance in HER2-overexpressing breast cancer cells via down-regulation of PTEN. Biochim Biophys Acta. 2017;1861:1970–1980. PubMed

Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Deng J, et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A. 2007;104:16158–16163. PubMed PMC

Moon SH, Kim DK, Cha Y, Jeon I, Song J, Park KS. PI3K/Akt and Stat3 signaling regulated by PTEN control of the cancer stem cell population, proliferation and senescence in a glioblastoma cell line. Int J Oncol. 2013;42:921–928. PubMed

Fantozzi A, Gruber DC, Pisarsky L, Heck C, Kunita A, Yilmaz M, et al. VEGF-mediated angiogenesis links EMT-induced cancer stemness to tumor initiation. Cancer Res. 2014;74:1566–1575. PubMed

Jinushi M, Chiba S, Yoshiyama H, Masutomi K, Kinoshita I, Dosaka-Akita H, et al. Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci U S A. 2011;108(30):12425. PubMed PMC

Yang J, Liao D, Chen C, Liu Y, Chuang TH, Xiang R, et al. Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells. 2013;31:248–258. PubMed

Attarha S, Roy A, Westermark B, Tchougounova E. Mast cells modulate proliferation, migration and stemness of glioma cells through downregulation of GSK3β expression and inhibition of STAT3 activation. Cell Signal. 2017;37:81–92. PubMed

Islam M, Sharma S, Teknos TN. RhoC regulates cancer stem cells in head and neck squamous cell carcinoma by overexpressing IL-6 and phosphorylation of STAT3. PLoS One. 2014;9:e88527. PubMed PMC

Zhao C, Li H, Lin HJ, Yang S, Lin J, Liang G. Feedback Activation of STAT3 as a Cancer Drug-Resistance Mechanism. Trends Pharmacol Sci. 2016;37:47–61. PubMed

Yang F, Van Meter TE, Buettner R, Hedvat M, Liang W, Kowolik CM, et al. Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas. Mol Cancer Ther. 2008;7:3519–3526. PubMed PMC

Nefedova Y, Nagaraj S, Rosenbauer A, Muro-Cacho C, Sebti SM, Gabrilovich DI. Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic-selective inhibition of the janus-activated kinase 2/signal transducers and activators of transcription 3 pathway. Cancer Res. 2005;65:9525–9535. PubMed PMC

Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell. 1998;2:305–316. PubMed

Chu WK, Dai PM, Li HL, Chen JK. Transcriptional activity of the DeltaNp63 promoter is regulated by STAT3. J Biol Chem. 2008;283:7328–7337. PubMed

Rufini S, Lena AM, Cadot B, Mele S, Amelio I, Terrinoni A, et al. The sterile alpha-motif (SAM) domain of p63 binds in vitro monoasialoganglioside (GM1) micelles. Biochem Pharmacol. 2011;82:1262–1268. PubMed

Sayan BS, Sayan AE, Yang AL, Aqeilan RI, Candi E, Cohen GM, et al. Cleavage of the transactivation-inhibitory domain of p63 by caspases enhances apoptosis. Proc Natl Acad Sci U S A. 2007;104:10871–10876. PubMed PMC

Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature. 1999;398:708–713. PubMed

Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature. 1999;398:714–718. PubMed

Pignon JC, Grisanzio C, Geng Y, Song J, Shivdasani RA, Signoretti S. p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia. Proc Natl Acad Sci U S A. 2013;110:8105–8110. PubMed PMC

Liu K, Jiang M, Lu Y, Chen H, Sun J, Wu S, et al. Sox2 cooperates with inflammation-mediated Stat3 activation in the malignant transformation of foregut basal progenitor cells. Cell Stem Cell. 2013;12:304–315. PubMed PMC

Sethi I, Sinha S, Buck MJ. Role of chromatin and transcriptional co-regulators in mediating p63-genome interactions in keratinocytes. BMC Genomics. 2014;15:1042. PubMed PMC

Wu M, Wang B, Gil J, Sabo E, Miller L, Gan L, et al. p63 and TTF-1 immunostaining. A useful marker panel for distinguishing small cell carcinoma of lung from poorly differentiated squamous cell carcinoma of lung. Am J Clin Pathol. 2003;119:696–702. PubMed

Chakrabarti R, Wei Y, Hwang J, Hang X, Andres Blanco M. Choudhury A, et al. ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling. Nat Cell Biol. 2014; 16. 1004-15:1–13. PubMed PMC

Koster MI, Lu SL, White LD, Wang XJ, Roop DR. Reactivation of developmentally expressed p63 isoforms predisposes to tumor development and progression. Cancer Res. 2006;66:3981–3986. PubMed

Wei W, Tweardy DJ, Zhang M, Zhang X, Landua J, Petrovic I, et al. STAT3 signaling is activated preferentially in tumor-initiating cells in claudin-low models of human breast cancer. Stem Cells. 2014;32:2571–2582. PubMed

Hajimoradi M, Mohammad Hassan Z, Ebrahimi M, Soleimani M, Bakhshi M, Firouzi J, et al. STAT3 is Overactivated in Gastric Cancer Stem-Like Cells. Cell J. 2016;17:617–628. PubMed PMC

Sriuranpong V, Park JI, Amornphimoltham P, Patel V, Nelkin BD, Gutkind JS. Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Cancer Res. 2003;63:2948–2956. PubMed

Thiagarajan PS, Zheng Q, Bhagrath M, Mulkearns-Hubert EE, Myers MG, Lathia JD, et al. STAT3 activation by leptin receptor is essential for TNBC stem cell maintenance. Endocr Relat Cancer. 2017;24:415–426. PubMed PMC

Chu WK, Lee KC, Chow SE, Chen JK. Dual regulation of the DeltaNp63 transcriptional activity by DeltaNp63 in human nasopharyngeal carcinoma cell. Biochem Biophys Res Commun. 2006;342:1356–1360. PubMed

Hsueh YJ, Chen HC, Chu WK, Cheng CC, Kuo PC, Lin LY, et al. STAT3 regulates the proliferation and differentiation of rabbit limbal epithelial cells via a ΔNp63-dependent mechanism. Invest Ophthalmol Vis Sci. 2011;52:4685–4693. PubMed

Ripamonti F, Albano L, Rossini A, Borrelli S, Fabris S, Mantovani R, et al. EGFR through STAT3 modulates ΔN63α expression to sustain tumor-initiating cell proliferation in squamous cell carcinomas. J Cell Physiol. 2013;228:871–878. PubMed

Ma J, Meng Y, Kwiatkowski DJ, Chen X, Peng H, Sun Q, et al. Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J Clin Invest. 2010;120:103–114. PubMed PMC

King KE, Ponnamperuma RM, Allen C, Lu H, Duggal P, Chen Z, et al. The p53 homologue DeltaNp63alpha interacts with the nuclear factor-kappaB pathway to modulate epithelial cell growth. Cancer Res. 2008;68:5122–5131. PubMed PMC

Yang X. Lu H, Yan B, Romano RA, Bian Y, Friedman J, et al. ΔNp63 versatilely regulates a Broad NF-κB gene program and promotes squamous epithelial proliferation, migration, and inflammation. Cancer Res. 2011;71:3688–3700. PubMed PMC

Senoo M, Matsumura Y, Habu S. TAp63gamma (p51A) and dNp63alpha (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression. Oncogene. 2002;21:2455–2465. PubMed

Stacy AJ, Craig MP, Sakaram S, Kadakia M. ΔNp63α and microRNAs: leveraging the epithelial-mesenchymal transition. Oncotarget. 2017;8:2114–2129. PubMed PMC

Sasaki Y, Ishida S, Morimoto I, Yamashita T, Kojima T, Kihara C, et al. The p53 family member genes are involved in the Notch signal pathway. J Biol Chem. 2002;277:719–724. PubMed

Su X, Napoli M, Abbas HA, Venkatanarayan A, Bui NHB, Coarfa C, et al. TAp63 suppresses mammary tumorigenesis through regulation of the Hippo pathway. Oncogene. 2017;36:2377–2393. PubMed PMC

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