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Interplay between signal transducers and activators of transcription (STAT) proteins and cancer: involvement, therapeutic and prognostic perspective

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Abstract

Signal transducers and activators of transcription or STAT are proteins that consist of various transcription factors that are responsible for activating genes regarding cell proliferation, differentiation, and apoptosis. They commonly activate several cytokine, growth, or hormone factors via the JAK-STAT signaling pathway by tyrosine phosphorylation which are responsible for giving rise to numerous immune responses. Mutations within the Janus-Kinases (JAKs) or the STATs can set off the commencement of various malfunctions of the immune system of the body; carcinogenesis being an inevitable outcome. STATs are known to act as both oncogenes and tumor suppressor genes which makes it a hot topic of investigation. Various STATs related mechanisms are currently being investigated to analyze its potential of serving as a therapeutic base for numerous immune diseases and cancer; a deeper understanding of the molecular mechanisms involved in the signaling pathways can contribute to the same. This review will throw light upon each STAT member in causing cancer malignancies by affecting subsequent signaling pathways and its genetic and epigenetic associations as well as various inhibitors that could be used to target these pathways thereby devising new treatment options. The review will also focus upon the therapeutic advances made in cancers that most commonly affect people and discuss how STAT genes are identified as prognostic markers.

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Abbreviations

STAT: :

Signal transducers and activators of transcription

JAK: :

Janus kinase

IFN: :

Interferon

DN: :

Dominant negative

EGF: :

Epidermal growth factor

PDGF: :

Platelet-derived growth factor

CSF-1::

Colony-stimulating factor 1

IL: :

Interleukin

BCL: :

B-cell lymphoma

TRADD::

Tumor necrosis factor receptor 1-associated death domain protein

Mdm2::

Murine double minute 2

c-Myc: :

Cellular myelocytomatosis oncogene

MHC: :

Major histocompatibility complex

bFGF: :

Basic fibroblast growth factor

PTEN/Akt: :

Phosphatase and tensin homolog deleted on chromosome 10/Ak strain transforming

HNSCC: :

head and neck squamous cell carcinoma

TRAIL: :

TNF-related apoptosis-inducing ligand

Fra-1: :

Fos-related antigen 1

TF: :

Transcription factor

FBXW7: :

F-box/WD repeat-containing protein 7

EGFR: :

Epidermal growth factor receptor

ISGF3: :

Interferon stimulated gene factor 3

VEGF: :

Vascular endothelial growth factor

MMP 2: :

Matrix metalloproteinase-2

HFIH: :

Hexane fraction of I. helenium

SH2: :

Src Homology 2

HBV: :

Hepatitis B virus

HCC: :

Hepatocellular carcinoma

DC: :

Dendritic cells

NOD: :

Nonobese diabetic

BM: :

Bone marrow

GM-CSF: :

Granulocyte–macrophage colony-stimulating factor

Tyk: :

Tyrosine kinase

SOCS: :

Suppressors of cytokine signaling proteins

CIS: :

Cytokine inhibitor Src homology 2-containing protein

PIAS: :

Protein inhibitors of activated STATs

ABC: :

ATP binding cassette

MCl -1: :

Myeloid cell leukemia 1

CML: :

Chronic myelogenous leukemia

AML: :

Acute myelogenous leukemia

FLT3-IND: :

FLT3 internal tandem duplication

MSM: :

Methylsufonylmethane

HER: :

Human epidermal growth factor receptor

ERK: :

Extracellular signal-regulated kinase

Th: :

T helper

IAP: :

Inhibitors of apoptosis proteins

Cdk: :

Cyclin-dependent kinases

DNMT: :

DNA methyltransferases

PCa: :

Prostate cancer

ADT: :

Androgen deprivation therapy

BRCA1: :

Breast Cancer gene 1

AR: :

Androgen receptor

ATF 3: :

Activating transcription factor 3

NSCLC: :

Non small cell lung cancer

CIN: :

Cervical intraepithelial neoplasia

TNBC: :

Triple negative breast cancer

OC: :

Ovarian cancer

CXCL: :

Chemokine ligand

EOC: :

Epithelial ovarian cancer

JNK: :

Jun N-terminal kinase

PAK: :

Serine/threonine-protein kinase

PPAR: :

Peroxisome proliferator-activated receptor

CRC: :

Colorectal cancers

COX: :

Cyclooxygenase

IL22RA1: :

Interleukin 22 receptor, alpha 1

OS: :

Overall survival

PDK4: :

Pyruvate Dehydrogenase Kinase 4

TCA:

Tricarboxylic acid

RAS:

Rat sarcoma

MAPK:

Mitogen-activated protein kinase

PI3K:

Phosphatidylinositol-3-kinase

AKT:

Protein kinase B

References

  1. Ihle JN. STATs: signal transducers and activators of transcription. Cell. 1996;84(3):331–4. https://doi.org/10.1016/s0092-8674(00)81277-5.

    Article  CAS  PubMed  Google Scholar 

  2. Loh CY, Arya A, Naema AF, Wong WF, Sethi G, Looi CY. Signal transducer and activator of transcription (stats) proteins in cancer and inflammation: functions and therapeutic implication. Front Oncol. 2019;21(9):48.

    Google Scholar 

  3. Benekli M, Baer MR, Baumann H, Wetzler M. Signal transducer and activator of transcription proteins in leukemias. Blood. 2003;101(8):2940–54. https://doi.org/10.1182/blood-2002-04-1204.

    Article  CAS  PubMed  Google Scholar 

  4. Meissl K, Macho-Maschler S, Müller M, Strobl B. The good and the bad faces of STAT1 in solid tumours. Cytokine. 2017;89:12–20.

    CAS  PubMed  Google Scholar 

  5. Hsu KS, Zhao X, Cheng X, et al. Dual regulation of Stat1 and Stat3 by the tumor suppressor protein PML contributes to interferon α-mediated inhibition of angiogenesis. J Biol Chem. 2017;292(24):10048–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Huang S, Bucana CD, Van Arsdall M, Fidler IJ. Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells. Oncogene. 2002;21(16):2504–12.

    CAS  PubMed  Google Scholar 

  7. Zhang X, Li X, Tan F, Yu N, Pei H. STAT1 Inhibits MiR-181a expression to suppress colorectal cancer cell proliferation through PTEN/Akt. J Cell Biochem. 2017;118(10):3435–43.

    CAS  PubMed  Google Scholar 

  8. Zhang Y, Liu Z. STAT1 in cancer: friend or foe? Discov Med. 2017;24(130):19–29.

    PubMed  Google Scholar 

  9. Xi S, Dyer KF, Kimak M, et al. Decreased STAT1 expression by promoter methylation in squamous cell carcinogenesis. J Natl Cancer Inst. 2006;98(3):181–9.

    CAS  PubMed  Google Scholar 

  10. Pitroda SP, Wakim BT, Sood RF, et al. STAT1-dependent expression of energy metabolic pathways links tumour growth and radioresistance to the Warburg effect. BMC Med. 2009;5(7):68.

    Google Scholar 

  11. Zhu H, Wang Z, Xu Q, et al. Inhibition of STAT1 sensitizes renal cell carcinoma cells to radiotherapy and chemotherapy. Cancer Biol Ther. 2012;13(6):401–7.

    CAS  PubMed  Google Scholar 

  12. Roberts D, Schick J, Conway S, et al. Identification of genes associated with platinum drug sensitivity and resistance in human ovarian cancer cells. Br J Cancer. 2005;92(6):1149–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Khodarev NN, Beckett M, Labay E, Darga T, Roizman B, Weichselbaum RR. STAT1 is overexpressed in tumors selected for radioresistance and confers protection from radiation in transduced sensitive cells. Proc Natl Acad Sci U S A. 2004;101(6):1714–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Choi EA, Lei H, Maron DJ, et al. Stat1-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand and the cell-surface death signaling pathway by interferon beta in human cancer cells. Cancer Res. 2003;63(17):5299–307.

    CAS  PubMed  Google Scholar 

  15. Zhang M, Liang L, He J, et al. Fra-1 inhibits cell growth and the warburg effect in cervical cancer cells via stat1 regulation of the p53 signaling pathway. Front Cell Dev Biol. 2020;30(8):579629.

    Google Scholar 

  16. Ry FZ, Farrar JD. STAT2: A shape-shifting anti-viral super STAT. JAKSTAT. 2013;2(1):e23633.

    Google Scholar 

  17. Verhoeven Y, Tilborghs S, Jacobs J, et al. The potential and controversy of targeting STAT family members in cancer. Semin Cancer Biol. 2020;60:41–56. https://doi.org/10.1016/j.semcancer.2019.10.002.

    Article  CAS  PubMed  Google Scholar 

  18. Steen HC, Gamero AM. STAT2 phosphorylation and signaling. JAKSTAT. 2013;2(4):e25790.

    PubMed  PubMed Central  Google Scholar 

  19. Lee CJ, An HJ, Cho ES, et al. Stat2 stability regulation: an intersection between immunity and carcinogenesis. Exp Mol Med. 2020;52(9):1526–36. https://doi.org/10.1038/s12276-020-00506-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ebersbach C, Beier AK, Thomas C, Erb HHH. Impact of STAT proteins in tumor progress and therapy resistance in advanced and metastasized prostate cancer. Cancers (Basel). 2021;13(19):4854.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen X, Huang J, Lü Y. High expression of STAT2 in ovarian cancer and its effect on metastasis of ovarian cancer cells. Nan Fang Yi Ke Da Xue Xue Bao. 2020;40(1):34–41.

    PubMed  Google Scholar 

  22. Liang Z, Gao LH, Cao LJ, et al. Detection of STAT2 in early stage of cervical premalignancy and in cervical cancer. Asian Pac J Trop Med. 2012;5(9):738–42.

    CAS  PubMed  Google Scholar 

  23. Gamero AM, Young MR, Mentor-Marcel R, et al. STAT2 contributes to promotion of colorectal and skin carcinogenesis. Cancer Prev Res (Phila). 2010;3(4):495–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Furth PA. STAT signaling in different breast cancer sub-types. Mol Cell Endocrinol. 2014;382(1):612–5.

    CAS  PubMed  Google Scholar 

  25. Uluer ET, Aydemir I, Inan S, Ozbilgin K, Vatansever HS. Effects of 5-fluorouracil and gemcitabine on a breast cancer cell line (MCF-7) via the JAK/STAT pathway. Acta Histochem. 2012;114(7):641–6.

    CAS  PubMed  Google Scholar 

  26. Schaber JD, Fang H, Xu J, Grimley PM, Rui H. Prolactin activates Stat1 but does not antagonize Stat1 activation and growth inhibition by type I interferons in human breast cancer cells. Cancer Res. 1998;58(9):1914–9.

    CAS  PubMed  Google Scholar 

  27. Ihle JN. The Stat family in cytokine signaling. Curr Opin Cell Biol. 2001;13(2):211–7.

    CAS  PubMed  Google Scholar 

  28. Kamran MZ, Patil P, Gude RP. Role of STAT3 in cancer metastasis and translational advances. Biomed Res Int. 2013;2013:421821.

    PubMed  PubMed Central  Google Scholar 

  29. Kanda N, Seno H, Konda Y, et al. STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene. 2004;23(28):4921–9.

    CAS  PubMed  Google Scholar 

  30. Dhir R, Ni Z, Lou W, DeMiguel F, Grandis JR, Gao AC. Stat3 activation in prostatic carcinomas. Prostate. 2002;51(4):241–6.

    CAS  PubMed  Google Scholar 

  31. Xie TX, Huang FJ, Aldape KD, et al. Activation of stat3 in human melanoma promotes brain metastasis. Cancer Res. 2006;66(6):3188–96.

    CAS  PubMed  Google Scholar 

  32. Ma JH, Qin L, Li X. Role of STAT3 signaling pathway in breast cancer. Cell Commun Signal. 2020;18(1):33.

    PubMed  PubMed Central  Google Scholar 

  33. Wang G, Chen JH, Qiang Y, Wang DZ, Chen Z. Decreased STAT4 indicates poor prognosis and enhanced cell proliferation in hepatocellular carcinoma. World J Gastroenterol. 2015;21(13):3983–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Verhoeven Y, Tilborghs S, Jacobs J, et al. The potential and controversy of targeting STAT family members in cancer. Semin Cancer Biol. 2020;60:41–56.

    CAS  PubMed  Google Scholar 

  35. Ronald Hoffman EJ, Leslie B, Silberstein E, et al. Hematology. 7th ed. Newyork: Elsevier; 2018. p. 163–75.

    Google Scholar 

  36. Yang Z, Chen M, Fialkow LB, Ellett JD, Wu R, Nadler JL. Inhibition of STAT4 activation by lisofylline is associated with the protection of autoimmune diabetes. Ann N Y Acad Sci. 2003;1005:409–11.

    PubMed  Google Scholar 

  37. Chiang PH, Wang L, Bonham CA, et al. Mechanistic insights into impaired dendritic cell function by rapamycin: inhibition of Jak2/Stat4 signaling pathway. J Immunol. 2004;172(3):1355–63.

    CAS  PubMed  Google Scholar 

  38. Lin JT, Martin SL, Xia L, Gorham JD. TGF-beta 1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet. J Immunol. 2005;174(10):5950–8.

    CAS  PubMed  Google Scholar 

  39. Kornfeld JW, Grebien F, Kerenyi MA, et al. The different functions of Stat5 and chromatin alteration through Stat5 proteins. Front Biosci. 2008;1(13):6237–54.

    Google Scholar 

  40. Walker SR, Xiang M, Frank DA. Distinct roles of STAT3 and STAT5 in the pathogenesis and targeted therapy of breast cancer. Mol Cell Endocrinol. 2014;382(1):616–21.

    CAS  PubMed  Google Scholar 

  41. Igelmann S, Neubauer HA, Ferbeyre G. STAT3 and STAT5 Activation in Solid Cancers. Cancers (Basel). 2019;11(10):1428.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Schepers H, van Gosliga D, Wierenga AT, Eggen BJ, Schuringa JJ, Vellenga E. STAT5 is required for long-term maintenance of normal and leukemic human stem/progenitor cells. Blood. 2007;110(8):2880–8.

    CAS  PubMed  Google Scholar 

  43. Talati PG, Gu L, Ellsworth EM, et al. Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer. Am J thol. 2015;185(9):2505–22.

    CAS  Google Scholar 

  44. Sumiyoshi H, Matsushita A, Nakamura Y, et al. Suppression of STAT5b in pancreatic cancer cells leads to attenuated gemcitabine chemoresistance, adhesion and invasion. Oncol Rep. 2016;35(6):3216–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Kollmann S, Grundschober E, Maurer B, et al. Twins with different personalities: STAT5B-but not STAT5A-has a key role in BCR/ABL-induced leukemia. Leukemia. 2019;33(7):1583–97. https://doi.org/10.1038/s41375-018-0369-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li Z, Chen C, Chen L, et al. STAT5a confers doxorubicin resistance to breast cancer by regulating ABCB1. Front Oncol. 2021;15(11):697950.

    Google Scholar 

  47. Maurer B, Kollmann S, Pickem J, Hoelbl-Kovacic A, Sexl V. STAT5A and STAT5B-Twins with Different Personalities in Hematopoiesis and Leukemia. Cancers (Basel). 2019;11(11):1726.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Nevalainen MT, Xie J, Torhorst J, et al. Signal transducer and activator of transcription-5 activation and breast cancer prognosis. J Clin Oncol. 2004;22(11):2053–60.

    CAS  PubMed  Google Scholar 

  49. Nelson EA, Walker SR, Weisberg E, et al. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood. 2011;117(12):3421–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Nelson EA, Walker SR, Xiang M, et al. The STAT5 inhibitor pimozide displays efficacy in models of acute myelogenous leukemia driven by FLT3 mutations. Genes Cancer. 2012;3(7–8):503–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Gallipoli P, Cook A, Rhodes S, et al. JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo. Blood. 2014;124(9):1492–501.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Lim EJ, Hong DY, Park JH, et al. Methylsulfonylmethane suppresses breast cancer growth by down-regulating STAT3 and STAT5b pathways. PLoS One. 2012;7(4):e33361.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Walker SR, Nelson EA, Zou L, et al. Reciprocal effects of STAT5 and STAT3 in breast cancer. Mol Cancer Res. 2009;7(6):966–76. https://doi.org/10.1158/1541-7786.MCR-08-0238.

    Article  CAS  PubMed  Google Scholar 

  54. Lee H, Kim JW, Choi DK, et al. Poziotinib suppresses ovarian cancer stem cell growth via inhibition of HER4-mediated STAT5 pathway. Biochem Biophys Res Commun. 2020;526(1):158–64. https://doi.org/10.1016/j.bbrc.2020.03.046.

    Article  CAS  PubMed  Google Scholar 

  55. Hideho Okada, Jacques Banchereau, Michael T Lotze. CHAPTER 10 - Interleukin-4, In:The Cytokine Handbook (Fourth Edition),Editor(s): Angus W. Thomson, Michael T. Lotze, Academic Press,2003,Pages 227–262,ISBN 9780126896633

  56. My Cancer Genome Genetically Informed Cancer Medicine; Available from: https://www.mycancergenome.org/content/gene/stat6/

  57. Delgado-Ramirez Y, Colly V, Gonzalez GV, Leon-Cabrera S. Signal transducer and activator of transcription 6 as a target in colon cancer therapy. Oncol Lett. 2020;20(1):455–64. https://doi.org/10.3892/ol.2020.11614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Binnemars-Postma K, Bansal R, Storm G, Prakash J. Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer. FASEB J. 2018;32(2):969–78. https://doi.org/10.1096/fj.201700629R.

    Article  CAS  PubMed  Google Scholar 

  59. Fu C, Jiang L, Hao S, et al. Activation of the IL-4/STAT6 signaling pathway promotes lung cancer progression by increasing M2 myeloid cells. Front Immunol. 2019;10:2638. https://doi.org/10.3389/fimmu.2019.02638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Clevenger CV. Roles and regulation of stat family transcription factors in human breast cancer. Am J Pathol. 2004;165(5):1449–60. https://doi.org/10.1016/S0002-9440(10)63403-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Alvarez JV, Frank DA. Genome-wide analysis of STAT target genes: elucidating the mechanism of STAT-mediated oncogenesis. Cancer Biol Ther. 2004;3(11):1045–50. https://doi.org/10.4161/cbt.3.11.1172.

    Article  CAS  PubMed  Google Scholar 

  62. Seghal PD. Epigenetic regulation of transcription factor STAT3 activity in cancer cells. Contemp Oncol/Współczesna Onkol. 2006;10(8):373–7.

    Google Scholar 

  63. Zhang Q, Wang HY, Woetmann A, Raghunath PN, Odum N, Wasik MA. STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes. Blood. 2006;108(3):1058–64. https://doi.org/10.1182/blood-2005-08-007377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wingelhofer B, Neubauer HA, Valent P, et al. Implications of STAT3 and STAT5 signaling on gene regulation and chromatin remodeling in hematopoietic cancer. Leukemia. 2018;32(8):1713–26. https://doi.org/10.1038/s41375-018-0117-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Leslie SW, Soon-Sutton TL, R I A, et al. Prostate Cancer. [Updated 2022 Nov 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470550/

  66. Ebersbach C, Beier AK, Thomas C, Erb HHH. Impact of STAT proteins in tumor progress and therapy resistance in advanced and metastasized prostate cancer. Cancers (Basel). 2021;13(19):4854. https://doi.org/10.3390/cancers13194854.

    Article  CAS  PubMed  Google Scholar 

  67. El-Habr EA, Levidou G, Trigka EA, et al. Complex interactions between the components of the PI3K/AKT/mTOR pathway, and with components of MAPK, JAK/STAT and Notch-1 pathways, indicate their involvement in meningioma development. Virchows Arch. 2014;465(4):473–85. https://doi.org/10.1007/s00428-014-1641-3.

    Article  CAS  PubMed  Google Scholar 

  68. da Silva HB, Amaral EP, Nolasco EL, et al. Dissecting major signaling pathways throughout the development of prostate cancer. Prostate Cancer. 2013;2013:920612. https://doi.org/10.1155/2013/920612.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Dutta P, Sabri N, Li J, Li WX. Role of STAT3 in lung cancer. JAKSTAT. 2015;3(4):e999503. https://doi.org/10.1080/21623996.2014.999503.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene. Cell. 1999;98(3):295–303. https://doi.org/10.1016/s0092-8674(00)81959-5.

    Article  CAS  PubMed  Google Scholar 

  71. Song L, Turkson J, Karras JG, Jove R, Haura EB. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene. 2023. https://doi.org/10.1038/sj.onc.1206479.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Cheng F, Wang HW, Cuenca A, et al. A critical role for Stat3 signaling in immune tolerance. Immunity. 2003;19(3):425–36. https://doi.org/10.1016/s1074-7613(03)00232-2.

    Article  CAS  PubMed  Google Scholar 

  73. Fowler JR, Maani EV, Dunton CJ, Jack BW. Cervical Cancer. Treasure Island (FL): StatPearls Publishing; 2022.

    Google Scholar 

  74. Gutiérrez-Hoya A, Soto-Cruz I. Role of the JAK/STAT pathway in cervical cancer: its relationship with HPV E6/E7 oncoproteins. Cells. 2020;9(10):2297. https://doi.org/10.3390/cells9102297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Liang Z, Gao LH, Cao LJ, et al. Detection of STAT2 in early stage of cervical premalignancy and in cervical cancer. Asian Pac J Trop Med. 2012;5(9):738–42. https://doi.org/10.1016/S1995-7645(12)60117-5.

    Article  CAS  PubMed  Google Scholar 

  76. Sun CY, Nie J, Huang JP, Zheng GJ, Feng B. Targeting STAT3 inhibition to reverse cisplatin resistance. Biomed Pharmacother. 2019;117:109135. https://doi.org/10.1016/j.canlet.2014.05.005.

    Article  CAS  PubMed  Google Scholar 

  77. Huang LL, Rao W. SiRNA interfering STAT3 enhances DDP sensitivity in cervical cancer cells. Eur Rev Med Pharmacol Sci. 2018;22(13):4098–106.

    PubMed  Google Scholar 

  78. Uluer ET, Aydemir I, Inan S, Ozbilgin K, Vatansever HS. Effects of 5-fluorouracil and gemcitabine on a breast cancer cell line (MCF-7) via the JAK/STAT pathway. Acta Histochem. 2012;114(7):641–6. https://doi.org/10.1016/j.acthis.2011.11.010.

    Article  CAS  PubMed  Google Scholar 

  79. Furth PA. STAT signaling in different breast cancer sub-types. Mol Cell Endocrinol. 2014;382(1):612–5. https://doi.org/10.1016/j.mce.2013.03.023.

    Article  CAS  PubMed  Google Scholar 

  80. Zhang WJ, Li BH, Yang XZ, et al. IL-4-induced Stat6 activities affect apoptosis and gene expression in breast cancer cells. Cytokine. 2008;42(1):39–47. https://doi.org/10.1016/j.cyto.2008.01.016.

    Article  CAS  PubMed  Google Scholar 

  81. Liang R, Chen X, Chen L, et al. STAT3 signaling in ovarian cancer: a potential therapeutic target. J Cancer. 2020;11(4):837–48. https://doi.org/10.7150/jca.35011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Groom JR, Luster AD. CXCR3 in T cell function. Exp Cell Res. 2011;317(5):620–31. https://doi.org/10.1016/j.yexcr.2010.12.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wu CJ, Sundararajan V, Sheu BC, Huang RY, Wei LH. Activation of STAT3 and STAT5 signaling in epithelial ovarian cancer progression: mechanism and therapeutic opportunity. Cancers (Basel). 2019;12(1):24. https://doi.org/10.3390/cancers12010024.

    Article  CAS  PubMed  Google Scholar 

  84. Rezaeeyan H, Hassani SN, Barati M, et al. PD-1/PD-L1 as a prognostic factor in leukemia. J Hematopathol. 2017;10:17–24. https://doi.org/10.1007/s12308-017-0293-z.

    Article  Google Scholar 

  85. Shahjahani M, Abroun A, Saki N, Bagher Mohammadi SM, Rezaeeyan H. STAT5: from pathogenesis mechanism to therapeutic approach in acute leukemia. Lab Med. 2020;51(4):345–51. https://doi.org/10.1093/labmed/lmz074.

    Article  PubMed  Google Scholar 

  86. Zhu CQ, Tsao MS. Prognostic markers in lung cancer: is it ready for prime time? Transl Lung Cancer Res. 2014;3(3):149–58. https://doi.org/10.3978/j.issn.2218-6751.2014.06.09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Li S, Sheng B, Zhao M, Shen Q, Zhu H, Zhu X. The prognostic values of signal transducers activators of transcription family in ovarian cancer. 2017. Biosci Rep. https://doi.org/10.1042/BSR20170650.

  88. Dong Z, Chen Y, Yang C, et al. STAT gene family mRNA expression and prognostic value in hepatocellular carcinoma. Onco Targets Ther. 2019;3(12):7175–91. https://doi.org/10.2147/OTT.S202122.

    Article  Google Scholar 

  89. Zhang J, Wang F, Liu F, Xu G. Predicting STAT1 as a prognostic marker in patients with solid cancer. Ther Adv Med Oncol. 2020;12:1758835920917558. https://doi.org/10.1177/1758835920917558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gordziel C, Bratsch J, Moriggl R, Knösel T, Friedrich K. Both STAT1 and STAT3 are favourable prognostic determinants in colorectal carcinoma. Br J Cancer. 2013;109(1):138–46. https://doi.org/10.1038/bjc.2013.274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Klupp F, Diers J, Kahlert C, et al. Expressional STAT3/STAT5 ratio is an independent prognostic marker in colon carcinoma. Ann Surg Oncol. 2015;22(Suppl 3):S1548–55. https://doi.org/10.1245/s10434-015-4485-4.

    Article  PubMed  Google Scholar 

  92. Liu X, He Z, Li CH, Huang G, Ding C, Liu H. Correlation analysis of JAK-STAT pathway components on prognosis of patients with prostate cancer. Pathol Oncol Res. 2012;18(1):17–23. https://doi.org/10.1007/s12253-011-9410-y.

    Article  CAS  PubMed  Google Scholar 

  93. Pang C, Gu Y, Ding Y, et al. Several genes involved in the JAK-STAT pathway may act as prognostic markers in pancreatic cancer identified by microarray data analysis. Medicine (Baltimore). 2018;97(50):e13297. https://doi.org/10.1097/MD.0000000000013297.

    Article  CAS  PubMed  Google Scholar 

  94. Tu Y, Zhong Y, Fu J, et al. Activation of JAK/STAT signal pathway predicts poor prognosis of patients with gliomas. Med Oncol. 2011;28(1):15–23. https://doi.org/10.1007/s12032-010-9435-1.

    Article  CAS  PubMed  Google Scholar 

  95. Oberhuber M, Pecoraro M, Rusz M, et al. STAT3-dependent analysis reveals PDK4 as independent predictor of recurrence in prostate cancer. Mol Syst Biol. 2020;16(4):e9247.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Chen HH, Chou CY, Wu YH, et al. Constitutive STAT5 activation correlates with better survival in cervical cancer patients treated with radiation therapy. Int J Radiat Oncol Biol Phys. 2012;82(2):658–66. https://doi.org/10.1016/j.ijrobp.2010.11.043.

    Article  CAS  PubMed  Google Scholar 

  97. Shi S, Ma HY, Zhang ZG. Clinicopathological and prognostic value of STAT3/p-STAT3 in cervical cancer: a meta and bioinformatics analysis. Pathol Res Pract. 2021;227:153624. https://doi.org/10.1016/j.prp.2021.153624.

    Article  CAS  PubMed  Google Scholar 

  98. Yu H, Jove R. The STATs of cancer–new molecular targets come of age. Nat Rev Cancer. 2004;4(2):97–105. https://doi.org/10.1038/nrc1275.

    Article  CAS  PubMed  Google Scholar 

  99. Guanizo AC, Fernando CD, Garama DJ, Gough DJ. STAT3: a multifaceted oncoprotein. Growth Factors. 2018;36(1–2):1–14.

    CAS  PubMed  Google Scholar 

  100. Bromberg J. Stat proteins and oncogenesis. J Clin Invest. 2002;109(9):1139–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Furqan M, Akinleye A, Mukhi N, Mittal V, Chen Y, Liu D. STAT inhibitors for cancer therapy. J Hematol Oncol. 2013;6:90. https://doi.org/10.1186/1756-8722-6-90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Sir C.V. Raman Research Park and Department of Biotechnology of SRM Institute of Science and Technology, Kattankulathur, Chennai, India for providing laboratory space.

Funding

This research was supported by the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Govt. of India (Sanction Order No. ECR/2016/000965).

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Authors and Affiliations

  1. Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603203, India

    Nandana Jill, Sannidhi Bhootra, Samiyah Kannanthodi, Geetha Shanmugam, Sudeshna Rakshit, Rohit Rajak, Vidhi Thakkar & Koustav Sarkar

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  1. Nandana Jill
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  2. Sannidhi Bhootra
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Contributions

KS contributed to Conceptualization, supervision and funding acquisition; SB, NJ, SK, RR, VT contributed to investigation, data curation, and writing of the original draft; SB, NJ, SK contributed to visualization; GS, SR, KS contributed to reviewing and editing of the manuscript.

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Correspondence to Koustav Sarkar.

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Jill, N., Bhootra, S., Kannanthodi, S. et al. Interplay between signal transducers and activators of transcription (STAT) proteins and cancer: involvement, therapeutic and prognostic perspective. Clin Exp Med 23, 4323–4339 (2023). https://doi.org/10.1007/s10238-023-01198-8

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