Signal Transducer and Activator of Transcription (STATs) Proteins in Cancer and Inflammation: Functions and Therapeutic Implication

Choy-Theng Loh1, Aditya Arya2, Ahmed Fadhil Naema3, Won Fen Wong4, Gautam Sethi5, Chung Yeng Looi1
1School of Biosciences, Faculty of Health and Medical Sciences, Taylor’s University, Subang Jaya, Malaysia
2School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
3Center of Biotechnology Researches, University of Al-Nahrain, Baghdad, Iraq
4Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
5Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

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Catlett-Falcone, 1999, Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells, Immunity, 10, 105, 10.1016/S1074-7613(00)80011-4

Grandis, 1998, Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth in vitro, J Clin Invest., 102, 1385, 10.1172/JCI3785

Lou, 2000, Interleukin-6 induces prostate cancer cell growth accompanied by activation of stat3 signaling pathway, Prostate, 42, 239, 10.1002/(SICI)1097-0045(20000215)42:3<239::AID-PROS10>3.0.CO;2-G

Zhang, 2002, Requirement of Stat3 signaling for HGF/SF-Met mediated tumorigenesis, Oncogene, 21, 217, 10.1038/sj.onc.1205004

Kaido, 2004, Interleukin-6 augments hepatocyte growth factor-induced liver regeneration; involvement of STAT3 activation, Hepatogastroenterology, 51, 1667

Hung, 2001, Co-operative effect of c-Src tyrosine kinase and Stat3 in activation of hepatocyte growth factor expression in mammary carcinoma cells, J Biol Chem., 276, 12395, 10.1074/jbc.M010715200

Garcia, 2001, Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells, Oncogene, 20, 2499, 10.1038/sj.onc.1204349

Bowman, 2000, STATs in oncogenesis, Oncogene, 19, 2474, 10.1038/sj.onc.1203527

Lin, 2000, STAT signaling in the pathogenesis and treatment of leukemias, Oncogene, 19, 2496, 10.1038/sj.onc.1203486

Schwaller, 2000, Stat5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2, Mol Cell, 6, 693, 10.1016/S1097-2765(00)00067-8

Bromberg, 1996, Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma, Proc Natl Acad Sci USA., 93, 7673, 10.1073/pnas.93.15.7673

Shankaran, 2001, IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity, Nature, 410, 1107, 10.1038/35074122

Gao, 2007, Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas, J Clin Invest., 117, 3846, 10.1172/JCI31871

Ernst, 2008, STAT3 and STAT1 mediate IL-11–dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice, J Clin Invest., 118, 1727, 10.1172/JCI34944

Arredondo, 2006, Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of α7 nicotinic receptor in oral keratinocytes, FASEB J., 20, 2093, 10.1096/fj.06-6191com

Sano, 2005, Signal transducer and activator of transcription 3 is a key regulator of keratinocyte survival and proliferation following UV irradiation, Cancer Res., 65, 5720, 10.1158/0008-5472.CAN-04-4359

O'shea, 2012, JAK and STAT signaling molecules in immunoregulation and immune-mediated disease, Immunity, 36, 542, 10.1016/j.immuni.2012.03.014

Rauch, 2013, The regulation of inflammation by interferons and their STATs, JAKSTAT, 2, e23820, 10.4161/jkst.23820

Rani, 2016, STAT5 in cancer and immunity, J Interferon Cytokine Res., 36, 226, 10.1089/jir.2015.0054

Glosson, 2012, Wheezing and itching: the requirement for STAT proteins in allergic inflammation, JAKSTAT, 1, 3, 10.4161/jkst.19086

O'shea, 2011, Genomic views of STAT function in CD4+ T helper cell differentiation, Nat Rev Immunol., 11, 239, 10.1038/nri2958

Stritesky, 2011, Changing the STATus quo in T helper cells, Transcription, 2, 179, 10.4161/trns.2.4.16614

Aggarwal, 2006, Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution, Ann N Y Acad Sci., 1091, 151, 10.1196/annals.1378.063

Chai, 2016, Targeting transcription factor STAT3 for cancer prevention and therapy, Pharmacol Ther., 162, 86, 10.1016/j.pharmthera.2015.10.004

Subramaniam, 2014, Possible involvement of signal transducer and activator of transcription-3 (STAT3) signaling pathway in the initiation and progression of hepatocellular carcinoma, Perspectives in Cancer Prevention-Translational Cancer Research, 73, 10.1007/978-81-322-1533-2_6

Wong, 2017, Do STAT3 inhibitors have potential in the future for cancer therapy?, Expert Opin Investig Drugs, 26, 883, 10.1080/13543784.2017.1351941

Wingelhofer, 2018, Implications of STAT3 and STAT5 signaling on gene regulation and chromatin remodeling in hematopoietic cancer, Leukemia, 32, 1713, 10.1038/s41375-018-0117-x

Able, 2017, STAT5-interacting proteins: a synopsis of proteins that regulate STAT5 activity, Biology (Basel), 6, 20, 10.3390/biology6010020

Hennighausen, 2008, Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B, Genes Dev., 22, 711, 10.1101/gad.1643908

Ihle, 2001, The Stat family in cytokine signaling, Curr Opin Cell Biol., 13, 211, 10.1016/S0955-0674(00)00199-X

Lee, 2017, Capsazepine inhibits JAK/STAT3 signaling, tumor growth, and cell survival in prostate cancer, Oncotarget, 8, 17700, 10.18632/oncotarget.10775

Darnell, 1997, STATs and gene regulation, Science, 277, 1630, 10.1126/science.277.5332.1630

Zhang, 2016, Nimbolide-induced oxidative stress abrogates STAT3 signaling cascade and inhibits tumor growth in transgenic adenocarcinoma of mouse prostate model, Antioxid Redox Signal., 24, 575, 10.1089/ars.2015.6418

Kim, 2018, Formononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model, Cancer Lett., 431, 123, 10.1016/j.canlet.2018.05.038

Lee, 2015, 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, 6, 6386, 10.18632/oncotarget.3443

Rajendran, 2012, Celastrol suppresses growth and induces apoptosis of human hepatocellular carcinoma through the modulation of STAT3/JAK2 signaling cascade in vitro and in vivo, Cancer Prev Res., 5, 631, 10.1158/1940-6207.CAPR-11-0420

Tormo, 2012, IL-6 activates STAT5 in T cells, Cytokine, 60, 575, 10.1016/j.cyto.2012.07.002

Leonard, 1998, Jaks and STATs: biological implications, Annu Rev Immunol., 16, 293, 10.1146/annurev.immunol.16.1.293

Stark, 1998, How Cells Respond to Interferons, 10.1146/annurev.biochem.67.1.227

Xue, 2002, Serine phosphorylation of Stat5 proteins in lymphocytes stimulated with IL-2, Int Immunol., 14, 1263, 10.1093/intimm/dxf101

Scheel, 2011, Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast, Cell, 145, 926, 10.1016/j.cell.2011.04.029

Zhang, 2017, Cardamonin represses proliferation, invasion, and causes apoptosis through the modulation of signal transducer and activator of transcription 3 pathway in prostate cancer, Apoptosis, 22, 158, 10.1007/s10495-016-1313-7

Liu, 2010, IL-6, a risk factor for hepatocellular carcinoma: FLLL32 inhibits IL-6-induced STAT3 phosphorylation in human hepatocellular cancer cells, Cell Cycle, 9, 3423, 10.4161/cc.9.17.12946

Mohan, 2014, Development of a novel azaspirane that targets the Janus kinase-signal transducer and activator of transcription (STAT) pathway in hepatocellular carcinoma in vitro and in vivo, J Biol Chem., 289, 34296, 10.1074/jbc.M114.601104

Baek, 2016, Resveratrol inhibits STAT3 signaling pathway through the induction of SOCS-1: role in apoptosis induction and radiosensitization in head and neck tumor cells, Phytomedicine, 23, 566, 10.1016/j.phymed.2016.02.011

Subramaniam, 2013, Potential role of signal transducer and activator of transcription (STAT) 3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma, Biochim Biophys Acta, 1835, 46, 10.1016/j.bbcan.2012.10.002

Kim, 2014, β-caryophyllene oxide inhibits constitutive and inducible STAT3 signaling pathway through induction of the SHP-1 protein tyrosine phosphatase, Mol Carcinog., 53, 793, 10.1002/mc.22035

Leaman, 1996, Regulation of STAT-dependent pathways by growth factors and cytokines, FASEB J., 10, 1578, 10.1096/fasebj.10.14.9002549

Hirano, 2000, Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors, Oncogene, 19, 2548, 10.1038/sj.onc.1203551

Kim, 2015, 6-Shogaol exerts anti-proliferative and pro-apoptotic effects through the modulation of STAT3 and MAPKs signaling pathways, Mol Carcinog., 54, 1132, 10.1002/mc.22184

Baek, 2017, Ginkgolic acid C 17: 1, derived from Ginkgo biloba leaves, suppresses constitutive and inducible STAT3 activation through induction of PTEN and SHP-1 tyrosine phosphatase, Molecules, 22, 276, 10.3390/molecules22020276

Haura, 2005, Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer, Nat Rev Clin Oncol., 2, 315, 10.1038/ncponc0195

Shanmugam, 2015, Abrogation of STAT3 signaling cascade by zerumbone inhibits proliferation and induces apoptosis in renal cell carcinoma xenograft mouse model, Mol Carcinog., 54, 971, 10.1002/mc.22166

Ma, 2006, Regulation of Stat3 nuclear import by importin α5 and importin α7 via two different functional sequence elements, Cell Signal., 18, 1117, 10.1016/j.cellsig.2005.06.016

Sethi, 2014, Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo, Mol Cancer, 13, 66, 10.1186/1476-4598-13-66

Jing, 2005, Targeting Stat3 in cancer therapy, Anticancer Drugs, 16, 601, 10.1097/00001813-200507000-00002

Lee, 2014, Capillarisin inhibits constitutive and inducible STAT3 activation through induction of SHP-1 and SHP-2 tyrosine phosphatases, Cancer Lett., 345, 140, 10.1016/j.canlet.2013.12.008

Siveen, 2014, Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors, Biochim Biophys Acta, 1845, 136, 10.1016/j.bbcan.2013.12.005

Li, 2010, Diosgenin, a steroidal saponin, inhibits STAT3 signaling pathway leading to suppression of proliferation and chemosensitization of human hepatocellular carcinoma cells, Cancer Lett., 292, 197, 10.1016/j.canlet.2009.12.003

Kannaiyan, 2011, Celastrol inhibits proliferation and induces chemosensitization through down-regulation of NF-κB and STAT3 regulated gene products in multiple myeloma cells, Br J Pharmacol., 164, 1506, 10.1111/j.1476-5381.2011.01449.x

Wen, 1997, JE, Nucleic Acids Res., 25, 2062, 10.1093/nar/25.11.2062

Kazansky, 1999, Differential effects of prolactin andsrc/abl kinases on the nuclear translocation of STAT5B and STAT5A, J Biol Chem., 274, 22484, 10.1074/jbc.274.32.22484

Rajendran, 2011, γ-Tocotrienol is a novel inhibitor of constitutive and inducible STAT3 signalling pathway in human hepatocellular carcinoma: potential role as an antiproliferative, pro-apoptotic and chemosensitizing agent, Br J Pharmacol., 163, 283, 10.1111/j.1476-5381.2010.01187.x

Turkson, 2000, STAT proteins: novel molecular targets for cancer drug discovery, Oncogene, 19, 6613, 10.1038/sj.onc.1204086

Li, 2013, Garcinol, a polyisoprenylated benzophenone modulates multiple pro-inflammatory signaling cascades leading to suppression of growth and survival of head and neck carcinoma, Cancer Prev Res., 6, 843, 10.1158/1940-6207.CAPR-13-0070

Silva, 2004, Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis, Oncogene, 23, 8017, 10.1038/sj.onc.1208159

Yamashita, 1998, Differential control of the phosphorylation state of proline-juxtaposed serine residues Ser725 of Stat5a and Ser730 of Stat5b in prolactin-sensitive cells, J Biol Chem., 273, 30218, 10.1074/jbc.273.46.30218

Wang, 2003, Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands, J Cell Biol., 161, 583, 10.1083/jcb.200212066

Park, 2001, Serine phosphorylation of GH-activated signal transducer and activator of transcription 5a (STAT5a) and STAT5b: impact on STAT5 transcriptional activity, Mol Endocrinol., 15, 2157, 10.1210/mend.15.12.0746

Shanmugam, 2011, Ursolic acid inhibits multiple cell survival pathways leading to suppression of growth of prostate cancer xenograft in nude mice, J Mol Med., 89, 713, 10.1007/s00109-011-0746-2

Rajendran, 2011, Suppression of signal transducer and activator of transcription 3 activation by butein inhibits growth of human hepatocellular carcinoma in vivo, Clin Cancer Res., 17, 1425, 10.1158/1078-0432.CCR-10-1123

Xiong, 2009, Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells, Lab Invest., 89, 717, 10.1038/labinvest.2009.11

Coffer, 2000, The role of STATs in myeloid differentiation and leukemia, Oncogene, 19, 2511, 10.1038/sj.onc.1203479

Ito, 2004, Oncogenic potential of the RUNX gene family: ‘overview’, Oncogene, 23, 4198, 10.1038/sj.onc.1207755

Cameron, 2004, The RUNX genes: lineage-specific oncogenes and tumor suppressors, Oncogene, 23, 4308, 10.1038/sj.onc.1207130

Osato, 2004, Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia, Oncogene, 23, 4284, 10.1038/sj.onc.1207779

Pratap, 2011, Metastatic bone disease: role of transcription factors and future targets, Bone, 48, 30, 10.1016/j.bone.2010.05.035

Thomas, 2004, Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma, J Cell Biol., 167, 925, 10.1083/jcb.200409187

Ito, 2005, RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization, Cancer Res., 65, 7743, 10.1158/0008-5472.CAN-05-0743

Ulloa, 1999, Inhibition of transforming growth factor-β/SMAD signalling by the interferon-γ/STAT pathway, Nature, 397, 710, 10.1038/17826

Li, 2002, Causal relationship between the loss of RUNX3 expression and gastric cancer, Cell, 109, 113, 10.1016/S0092-8674(02)00690-6

Yano, 2006, The RUNX3 tumor suppressor upregulates bim in gastric epithelial cells undergoing transforming growth factorβ-induced apoptosis, Mol Cell Biol., 26, 4474, 10.1128/MCB.01926-05

Zheng, 2018, DNA methylation affects metastasis of renal cancer and is associated with TGF-β/RUNX3 inhibition, Cancer Cell Int., 18, 56, 10.1186/s12935-018-0554-7

Nakashima, 1999, Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300, Science, 284, 479, 10.1126/science.284.5413.479

Kim, 2003, Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation, Genes Dev., 17, 1979, 10.1101/gad.1119303

Miyazono, 2004, Coordinate regulation of cell growth and differentiation by TGF-β superfamily and RUNX proteins, Oncogene, 23, 4232, 10.1038/sj.onc.1207131

Levine, 1991, The p53 tumour suppressor gene, Nature, 351, 453, 10.1038/351453a0

Niu, 2005, Role of Stat3 in regulating p53 expression and function, Mol Cell Biol., 25, 7432, 10.1128/MCB.25.17.7432-7440.2005

Chin, 1996, Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21WAF1/CIP1 mediated by STAT1, Science, 272, 719, 10.1126/science.272.5262.719

Macleod, 1995, p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage, Genes Dev., 9, 935, 10.1101/gad.9.8.935

Townsend, 2004, STAT-1 interacts with p53 to enhance DNA damage-induced apoptosis, J Biol Chem., 279, 5811, 10.1074/jbc.M302637200

Kaplan, 1998, Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice, Proc Natl Acad Sci USA., 95, 7556, 10.1073/pnas.95.13.7556

Haupt, 1997, Mdm2 promotes the rapid degradation of p53, Nature, 387, 296, 10.1038/387296a0

Baran-Marszak, 2004, Differential roles of STAT1α and STAT1β in fludarabine-induced cell cycle arrest and apoptosis in human B cells, Blood, 104, 2475, 10.1182/blood-2003-10-3508

Youlyouz-Marfak, 2008, Identification of a novel p53-dependent activation pathway of STAT1 by antitumour genotoxic agents, Cell Death Differ., 15, 376, 10.1038/sj.cdd.4402270

Gamero, 2018, p53 inactivation and STAT2 cooperate to enhance migration and metastasis of colon tumor cells, AACR, 10.1158/1538-7445.AM2018-3157

Mantovani, 2008, Cancer-related inflammation, Nature, 454, 436, 10.1038/nature07205

Karin, 2005, NF-κB: linking inflammation and immunity to cancer development and progression, Nat Rev Immunol., 5, 749, 10.1038/nri1703

Baud, 2009, Is NF-κB a good target for cancer therapy?, Nature Rev Drug Discov., 8, 33, 10.1038/nrd2781

Bollrath, 2009, gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis, Cancer Cell, 15, 91, 10.1016/j.ccr.2009.01.002

Grivennikov, 2009, IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer, Cancer Cell, 15, 103, 10.1016/j.ccr.2009.01.001

Lee, 2009, Persistently activated Stat3 maintains constitutive NF-κB activity in tumors, Cancer Cell, 15, 283, 10.1016/j.ccr.2009.02.015

Yang, 2007, Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB, Genes Dev., 21, 1396, 10.1101/gad.1553707

Bromberg, 1999, Stat3 as an oncogene, Cell, 98, 295, 10.1016/S0092-8674(00)81959-5

Yu, 2007, Tumour immunology: crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment, Nat Rev Immunol., 7, 41, 10.1038/nri1995

Basseres, 2006, Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression, Oncogene, 25, 6817, 10.1038/sj.onc.1209942

Zhong, 1994, Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6, Science, 264, 95, 10.1126/science.8140422

Yu, 2004, The STATs of cancer—new molecular targets come of age, Nat Rev Cancer, 4, 97, 10.1038/nrc1275

Ogura, 2008, Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction, Immunity, 29, 628, 10.1016/j.immuni.2008.07.018

Pandurangan, 2014, Signal transducer and activator of transcription 3-a promising target in colitis-associated cancer, Asian Pac J Cancer Prev., 15, 551, 10.7314/apjcp.2014.15.2.551

Murone, 2016, Debio 0617B inhibits growth of STAT3-driven solid tumors through combined inhibition of JAK, SRC, and class III/V receptor tyrosine kinases, Mol Cancer Ther., 15, 2334, 10.1158/1535-7163.MCT-15-0974

Wu, 2015, FDA-approved small-molecule kinase inhibitors, Trends Pharmacol Sci., 36, 422, 10.1016/j.tips.2015.04.005

Pei, 2018, Discovery of a highly selective JAK3 inhibitor for the treatment of rheumatoid arthritis, Sci Rep., 8, 5273, 10.1038/s41598-018-23569-y

Ghoreschi, 2009, Janus kinases in immune cell signaling, Immunol Rev., 228, 273, 10.1111/j.1600-065X.2008.00754.x

Gehringer, 2014, Novel Hinge-binding motifs for janus kinase 3 inhibitors: a comprehensive structure–activity relationship study on tofacitinib bioisosteres, ChemMedChem, 9, 2516, 10.1002/cmdc.201402252

Winthrop, 2017, The emerging safety profile of JAK inhibitors in rheumatic disease, Nat Rev Rheumatol., 13, 234, 10.1038/nrrheum.2017.23

Lavecchia, 2011, STAT-3 inhibitors: state of the art and new horizons for cancer treatment, Curr Med Chem., 18, 2359, 10.2174/092986711795843218

Buettner, 2002, Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention, Clin Cancer Res., 8, 945

Furqan, 2013, STAT inhibitors for cancer therapy, J Hematol Oncol., 6, 90, 10.1186/1756-8722-6-90

Wingelhofer, 2018, Pharmacologic inhibition of STAT5 in acute myeloid leukemia, Leukemia, 32, 1135, 10.1038/s41375-017-0005-9

Nelson, 2011, The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors, Blood, 117, 3421, 10.1182/blood-2009-11-255232

Arora, 2018, The role of signal transducer and activator of transcription 3 (STAT3) and its targeted inhibition in hematological malignancies, Cancers (Basel), 10, 327, 10.3390/cancers10090327

Shin, 2009, Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells, Cancer Res., 69, 193, 10.1158/0008-5472.CAN-08-2575

Bhutani, 2007, Capsaicin is a novel blocker of constitutive and interleukin-6–inducible STAT3 activation, Clin Cancer Res., 13, 3024, 10.1158/1078-0432.CCR-06-2575

Bharti, 2003, Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells, J Immunol., 171, 3863, 10.4049/jimmunol.171.7.3863

Oi, 2016, STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma, Int J Oncol., 49, 2275, 10.3892/ijo.2016.3757

Amit-Vazina, 2005, Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells, Br J Cancer, 93, 70, 10.1038/sj.bjc.6602637

Pinz, 2014, The natural chemopreventive agent sulforaphane inhibits STAT5 activity, PLoS ONE, 9, e99391, 10.1371/journal.pone.0099391

Alshamsan, 2010, The induction of tumor apoptosis in B16 melanoma following STAT3 siRNA delivery with a lipid-substituted polyethylenimine, Biomaterials, 31, 1420, 10.1016/j.biomaterials.2009.11.003

Turkson, 2004, STAT proteins as novel targets for cancer drug discovery, Expert Opin Ther Targets, 8, 409, 10.1517/14728222.8.5.409

Anastasov, 2009, Efficient shRNA delivery into B and T lymphoma cells using lentiviral vector-mediated transfer, J Hematopathol., 2, 9, 10.1007/s12308-008-0020-x

Peer, 2011, Special delivery: targeted therapy with small RNAs, Gene Ther., 18, 1127, 10.1038/gt.2011.56

Weinstein, 2016, Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies, Proc Natl Acad Sci USA., 113, E16, 10.1073/pnas.1519273113

de Fougerolles, 2007, Interfering with disease: a progress report on siRNA-based therapeutics, Nat Rev Drug Discov., 6, 443, 10.1038/nrd2310

Paddison, 2002, Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells, Genes Dev., 16, 948, 10.1101/gad.981002

Konnikova, 2003, Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells, BMC Cancer, 3, 23, 10.1186/1471-2407-3-23

Konnikova, 2005, Signal transducer and activator of transcription 3 (STAT3) regulates human telomerase reverse transcriptase (hTERT) expression in human cancer and primary cells, Cancer Res., 65, 6516, 10.1158/0008-5472.CAN-05-0924

Cao, 2011, STAT5 regulates glioma cell invasion by pathways dependent and independent of STAT5 DNA binding, Neurosci Lett., 487, 228, 10.1016/j.neulet.2010.10.028

Gu, 2010, Stat5 promotes metastatic behavior of human prostate cancer cells in vitro and in vivo, Endocr Relat Cancer, 17, 481, 10.1677/ERC-09-0328

Choi, 2011, Granulocyte macrophage-colony stimulating factor shows anti-apoptotic activity in neural progenitor cells via JAK/STAT5-Bcl-2 pathway, Apoptosis, 16, 127, 10.1007/s10495-010-0552-2

Gao, 2005, Inhibition of STAT3 expression by siRNA suppresses growth and induces apoptosis in laryngeal cancer cells, Acta Pharmacol Sin., 26, 377, 10.1111/j.1745-7254.2005.00053.x

Jin, 2010, The effect of STAT5 silenced by siRNA on proliferation, apoptosis and invasion of esophageal carcinoma cell line EC9706, Chinese German J Clin Oncol., 9, 692, 10.1007/s10330-010-0717-z

Kunigal, 2009, Stat3-siRNA induces Fas-mediated apoptosis in vitro and in vivo in breast cancer, Int J Oncol., 34, 1209, 10.3892/ijo_00000249

Xiong, 2012, Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition, J Biol Chem., 287, 5819, 10.1074/jbc.M111.295964

Xu, 2013, The upregulation of signal transducer and activator of transcription 5-dependent microRNA-182 and microRNA-96 promotes ovarian cancer cell proliferation by targeting forkhead box O3 upon leptin stimulation, Int J Biochem Cell Biol., 45, 536, 10.1016/j.biocel.2012.12.010

Zhang, 2016, SENP1 regulates hepatocyte growth factor-induced migration and epithelial-mesenchymal transition of hepatocellular carcinoma, Tumour Biol., 37, 7741, 10.1007/s13277-015-4406-y

Tatiparti, 2017, siRNA delivery strategies: a comprehensive review of recent developments, Nanomaterials, 7, 77, 10.3390/nano7040077

Guven, 2005, Efficient gene transfer into primary human natural killer cells by retroviral transduction, Exp Hematol., 33, 1320, 10.1016/j.exphem.2005.07.006

Yang, 2009, Lentivirus-mediated shRNA interference targeting STAT3 inhibits human pancreatic cancer cell invasion, World J Gastroenterol., 15, 3757, 10.3748/wjg.15.3757

Emeagi, 2013, Downregulation of Stat3 in melanoma: reprogramming the immune microenvironment as an anticancer therapeutic strategy, Gene Ther., 20, 1085, 10.1038/gt.2013.35

Wang, 2012, Delivery of interferons and siRNA targeting STAT3 using lentiviral vectors suppresses the growth of murine melanoma, Cancer Gene Ther., 19, 822, 10.1038/cgt.2012.65

Cao, 2011, EGF stimulates cyclooxygenase-2 expression through the STAT5 signaling pathway in human lung adenocarcinoma A549 cells, Int J Oncol., 39, 383, 10.3892/ijo.2011.1053

Zhang, 2007, Cationic lipids and polymers mediated vectors for delivery of siRNA, J Control Release, 123, 1, 10.1016/j.jconrel.2007.07.016

Zhao, 2015, Knockdown of STAT3 expression in SKOV3 cells by biodegradable siRNA–PLGA/CSO conjugate micelles, Colloids Surf B Biointerfaces, 127, 155, 10.1016/j.colsurfb.2015.01.034

Hou, 2013, Melittin derived peptides for nanoparticle based siRNA transfection, Biomaterials, 34, 3110, 10.1016/j.biomaterials.2013.01.037

Soenen, 2009, Addressing the problem of cationic lipid-mediated toxicity: the magnetoliposome model, Biomaterials, 30, 3691, 10.1016/j.biomaterials.2009.03.040

Ballarín-González, 2012, Polycation-based nanoparticle delivery of RNAi therapeutics: adverse effects and solutions, Adv Drug Deliv Rev., 64, 1717, 10.1016/j.addr.2012.07.004

Forti, 2016, A bridge to silencing: Co-assembling anionic nanoparticles of siRNA and hyaluronan sulfate via calcium ion bridges, J Control Release, 232, 215, 10.1016/j.jconrel.2016.04.033

Lv, 2006, Toxicity of cationic lipids and cationic polymers in gene delivery, J Control Release, 114, 100, 10.1016/j.jconrel.2006.04.014

Alshamsan, 2008, Formulation and delivery of siRNA by oleic acid and stearic acid modified polyethylenimine, Mol Pharma., 6, 121, 10.1021/mp8000815

Das, 2014, Assessment of drug delivery and anticancer potentials of nanoparticles-loaded siRNA targeting STAT3 in lung cancer, in vitro and in vivo, Toxicol Lett., 225, 454, 10.1016/j.toxlet.2014.01.009

Su, 2012, PLGA nanoparticles codeliver paclitaxel and Stat3 siRNA to overcome cellular resistance in lung cancer cells, Int J Nanomed., 7, 4269, 10.2147/IJN.S33666

Yin, 2013, Functional graphene oxide as a plasmid-based Stat3 siRNA carrier inhibits mouse malignant melanoma growth in vivo, Nanotechnology, 24, 105102, 10.1088/0957-4484/24/10/105102

Yuan, 2011, Recent advances of siRNA delivery by nanoparticles, Expert Opin Drug Deliv., 8, 521, 10.1517/17425247.2011.559223

Heo, 2014, Programmed nanoparticles for combined immunomodulation, antigen presentation and tracking of immunotherapeutic cells, Biomaterials, 35, 590, 10.1016/j.biomaterials.2013.10.009

Molavi, 2010, Development of a poly (d, l-lactic-co-glycolic acid) nanoparticle formulation of STAT3 inhibitor JSI-124: implication for cancer immunotherapy, Mol Pharma., 7, 364, 10.1021/mp900145g

Labala, 2017, Effective melanoma cancer suppression by iontophoretic co-delivery of STAT3 siRNA and imatinib using gold nanoparticles, Int J Pharma., 525, 407, 10.1016/j.ijpharm.2017.03.087

Labala, 2016, Transcutaneous iontophoretic delivery of STAT3 siRNA using layer-by-layer chitosan coated gold nanoparticles to treat melanoma, Colloids Surf B Biointerfaces, 146, 188, 10.1016/j.colsurfb.2016.05.076

Tan, 2005, Surface modification of gold and quantum dot nanoparticles with chitosan for bioapplications, J Biomed Mater Res A, 75, 56, 10.1002/jbm.a.30410

Liang, 2011, Plasmid-based Stat3 siRNA delivered by hydroxyapatite nanoparticles suppresses mouse prostate tumour growth in vivo, Asian J Androl., 13, 481, 10.1038/aja.2010.167

Shi, 2018, Inorganic kernel-Supported asymmetric hybrid vesicles for targeting delivery of STAT3-decoy oligonucleotides to overcome anti-HER2 therapeutic resistance of BT474R, J Control Release, 279, 53, 10.1016/j.jconrel.2018.04.023

Luo, 2015, Nanovaccine loaded with poly I: C and STAT3 siRNA robustly elicits anti-tumor immune responses through modulating tumor-associated dendritic cells in vivo, Biomaterials, 38, 50, 10.1016/j.biomaterials.2014.10.050

Ou, 2018, Regulatory T cell-targeted hybrid nanoparticles combined with immuno-checkpoint blockage for cancer immunotherapy, J Control Release, 281, 84, 10.1016/j.jconrel.2018.05.018

Larmonier, 2008, Imatinib mesylate inhibits CD4+ CD25+ regulatory T cell activity and enhances active immunotherapy against BCR-ABL− tumors, J Immunol., 181, 6955, 10.4049/jimmunol.181.10.6955

Kim, 2012, Nanoparticle delivery of a peptide targeting EGFR signaling, J Control Release, 157, 279, 10.1016/j.jconrel.2011.08.014

Liu, 2013, Curcumin ameliorates dextran sulfate sodium-induced experimental colitis by blocking STAT3 signaling pathway, Int Immunopharmacol., 17, 314, 10.1016/j.intimp.2013.06.020

Rathore, 2008, Simultaneous determination of hydrazinocurcumin and phenol red in samples from rat intestinal permeability studies: HPLC method development and validation, J Pharma Biomed Anal., 46, 374, 10.1016/j.jpba.2007.09.019

Zhang, 2013, Hydrazinocurcumin encapsuled nanoparticles “re-educate” tumor-associated macrophages and exhibit anti-tumor effects on breast cancer following STAT3 suppression, PLoS ONE, 8, e65896, 10.1371/journal.pone.0065896

Liao, 2011, Synthetic enzyme inhibitor: a novel targeting ligand for nanotherapeutic drug delivery inhibiting tumor growth without systemic toxicity, Nanomedicine, 7, 665, 10.1016/j.nano.2011.03.001

Guorgui, 2018, Curcumin formulated in solid lipid nanoparticles has enhanced efficacy in Hodgkin's lymphoma in mice, Arch Biochem Biophys., 648, 12, 10.1016/j.abb.2018.04.012

Ma, 2015, STAT3 decoy oligodeoxynucleotides-loaded solid lipid nanoparticles induce cell death and inhibit invasion in ovarian cancer cells, PLoS ONE, 10, e0124924, 10.1371/journal.pone.0124924

Kotmakçi, 2017, Preparation and characterization of lipid nanoparticle/pDNA complexes for STAT3 downregulation and overcoming chemotherapy resistance in lung cancer cells, Int J Pharma., 525, 101, 10.1016/j.ijpharm.2017.04.034

Xu, 2014, A meta-analysis of STAT3 and phospho-STAT3 expression and survival of patients with non-small-cell lung cancer, Eur J Surg Oncol., 40, 311, 10.1016/j.ejso.2013.11.012

Shahzad, 2011, Targeted delivery of small interfering RNA using reconstituted high-density lipoprotein nanoparticles, Neoplasia, 13, 309, 10.1593/neo.101372

Ruvinov, 2015, Calcium–siRNA nanocomplexes: what reversibility is all about, J Control Release, 203, 150, 10.1016/j.jconrel.2015.02.029

Bondalapati, 2014, Rapid end-group modification of polysaccharides for biomaterial applications in regenerative medicine, Macromol Rapid Commun., 35, 1754, 10.1002/marc.201400354

Korin, 2017, GalNAc bio-functionalization of nanoparticles assembled by electrostatic interactions improves siRNA targeting to the liver, J Control Release, 266, 310, 10.1016/j.jconrel.2017.10.001

de Almeida, 2017, Aptamer delivery of siRNA, radiopharmaceutics and chemotherapy agents in cancer, Int J Pharma., 525, 334, 10.1016/j.ijpharm.2017.03.086

Esposito, 2018, STAT3 gene silencing by aptamer-siRNA chimera as selective therapeutic for glioblastoma, Mol Ther Nucleic Acids, 10, 398, 10.1016/j.omtn.2017.12.021

Akhavan, 2013, De-repression of PDGFRβ transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients, Cancer Discov., 3, 534, 10.1158/2159-8290.CD-12-0502

Najar, 2013, EGFR antisense oligonucleotides encapsulated with nanoparticles decrease EGFR, MAPK1 and STAT5 expression in a human colon cancer cell line, Asian Pac J Cancer Prev., 14, 495, 10.7314/apjcp.2013.14.1.495

Jiang, 2016, Eradication of acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles, Cancer Res., 76, 4470, 10.1158/0008-5472.CAN-15-2949

Théry, 2002, Exosomes: composition, biogenesis and function, Nat Rev Immunol., 2, 569, 10.1038/nri855

Zhang, 2018, Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation, Nat Cell Biol., 20, 332, 10.1038/s41556-018-0040-4