Table Info

Table 1.

STAT3 functions and its activators

Function	Activator	Target genes	References
Angiogenesis	IL-6, VEGF, FGF, IL-17	PDGF, VEGF, TNF-α, TGF-β, c-Jun	[6, 21–26]
Cell proliferation	EGF, IL-6, LDL, PRL	c-Myc, cyclin-D1	[20, 27–29]
Immune escape	IL-6, IL-10, CXCL12, EGF, IL-22	IL-6, IL-10, PD-L1, arginase 1	[6, 27, 28, 30, 31]
Metastasis	IL-6, IL-28, PRL, CXCL12, LDL	Snail, slug, MMPs, TWIST, ZEB1	[6, 20, 29, 32]
Survival	IL-6, LDL, PRL, FGF	Bcl-XL, Mcl-1, survivin	[29, 33, 34]
Stemness	IL-22, PRL, IL-6	Sox2, Nanog, c-Myc	[20, 32, 35, 36]

LDL: low-density lipoprotein; CXCL12: CXC chemokine (CXC) ligand 12; c-Jun: Jun proto-oncogene; c-Myc: Myc proto-oncogene; MMPs: matrix metalloproteinases; TWIST: class A basic helix-loop-helix protein 38; ZEB1: zinc finger E-box-binding homeobox 1; Bcl-XL: B-cell lymphoma-extra large; Mcl-1: induced myeloid leukemia cell differentiation protein; Sox2: SRY-box 2

Declarations

Author contributions

ZH: Conceptualization. ZH and SS: Writing—original draft. DS and SA: Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Konigsberg J. American cancer society facts & figures 2023 [Internet]. American Cancer Society; 2023 [cited 2023 Jul 20]. Available from: https://www.acsresources.org/uncategorized/american-cancer-society-facts-figures-2023/#:~:text=The%20American%20Cancer%20Society%20estimates%20that%20in%202023,increase%20compared%20to%20the%202022%20estimate%20of%20609%2C360

Sarantis P, Koustas E, Papadimitropoulou A, Papavassiliou AG, Karamouzis MV. Pancreatic ductal adenocarcinoma: treatment hurdles, tumor microenvironment and immunotherapy. World J Gastrointest Oncol. 2020;12:173–81. [DOI] [PubMed] [PMC]

Hu JX, Zhao CF, Chen WB, Liu QC, Li QW, Lin YY, et al. Pancreatic cancer: a review of epidemiology, trend, and risk factors. World J Gastroenterol. 2021;27:4298–321. [DOI] [PubMed] [PMC]

Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–21. Erratum in: Cancer Res. 2014;74:4006. [DOI] [PubMed]

Song Y, Tang MY, Chen W, Wang Z, Wang SL. High JAK2 protein expression predicts a poor prognosis in patients with resectable pancreatic ductal adenocarcinoma. Dis Markers. 2020;2020:7656031. [DOI] [PubMed] [PMC]

Al-Hetty HRAK, Abdulameer SJ, Alkubaisy SA, Zaid SA, Jalil AT, Jasim IK. STAT3 signaling in pancreatic ductal adenocarcinoma: a candidate therapeutic target. Pathol Res Pract. 2023;245:154425. [DOI] [PubMed]

Shahmarvand N, Nagy A, Shahryari J, Ohgami RS. Mutations in the signal transducer and activator of transcription family of genes in cancer. Cancer Sci. 2018;109:926–33. [DOI] [PubMed] [PMC]

Huang C, Yang G, Jiang T, Zhu G, Li H, Qiu Z. The effects and mechanisms of blockage of STAT3 signaling pathway on IL-6 inducing EMT in human pancreatic cancer cells in vitro. Neoplasma. 2011;58:396–405. [DOI] [PubMed]

Nagathihalli NS, Castellanos JA, VanSaun MN, Dai X, Ambrose M, Guo Q, et al. Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells. Oncotarget. 2016;7:65982–92. [DOI] [PubMed] [PMC]

10.

Dandawate P, Kaushik G, Ghosh C, Standing D, Ali Sayed AA, Choudhury S, et al. Diphenylbutylpiperidine antipsychotic drugs inhibit prolactin receptor signaling to reduce growth of pancreatic ductal adenocarcinoma in mice. Gastroenterology. 2020;158:1433–49.E27. [DOI] [PubMed] [PMC]

11.

Bu LL, Yu GT, Wu L, Mao L, Deng WW, Liu JF, et al. STAT3 induces immunosuppression by upregulating PD-1/PD-L1 in HNSCC. J Dent Res. 2017;96:1027–34. [DOI] [PubMed] [PMC]

12.

Lefler JE, MarElia-Bennett CB, Thies KA, Hildreth BE 3rd, Sharma SM, Pitarresi JR, et al. STAT3 in tumor fibroblasts promotes an immunosuppressive microenvironment in pancreatic cancer. Life Sci Alliance. 2022;5:e202201460. [DOI] [PubMed] [PMC]

13.

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;13:4854. [DOI] [PubMed] [PMC]

14.

Awasthi N, Liongue C, Ward AC. STAT proteins: a kaleidoscope of canonical and non-canonical functions in immunity and cancer. J Hematol Oncol. 2021;14:198. [DOI] [PubMed] [PMC]

15.

Standing D, Feess E, Kodiyalam S, Kuehn M, Hamel Z, Johnson J, et al. The role of STATs in ovarian cancer: exploring their potential for therapy. Cancers (Basel). 2023;15:2485. [DOI] [PubMed] [PMC]

16.

Zhang T, Kee WH, Seow KT, Fung W, Cao X. The coiled-coil domain of Stat3 is essential for its SH2 domain-mediated receptor binding and subsequent activation induced by epidermal growth factor and interleukin-6. Mol Cell Biol. 2000;20:7132–9. [DOI] [PubMed] [PMC]

17.

Yu Z, Kone BC. The STAT3 DNA-binding domain mediates interaction with NF-κB p65 and inducible nitric oxide synthase transrepression in mesangial cells. J Am Soc Nephrol. 2004;15:585–91. [DOI] [PubMed]

18.

Lee H, Jeong AJ, Ye SK. Highlighted STAT3 as a potential drug target for cancer therapy. BMB Rep. 2019;52:415–23. [DOI] [PubMed] [PMC]

19.

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

20.

Standing D, Dandawate P, Anant S. Prolactin receptor signaling: a novel target for cancer treatment - exploring anti-PRLR signaling strategies. Front Endocrinol (Lausanne). 2023;13:1112987. [DOI] [PubMed] [PMC]

21.

Rapp J, Jung M, Klar RFU, Wolf J, Arnold J, Gorka O, et al. STAT3 signaling induced by the IL-6 family of cytokines modulates angiogenesis. J Cell Sci. 2023;136:jcs260182. [DOI] [PubMed]

22.

van Duijneveldt G, Griffin MDW, Putoczki TL. Emerging roles for the IL-6 family of cytokines in pancreatic cancer. Clin Sci (Lond). 2020;134:2091–115. [DOI] [PubMed] [PMC]

23.

Longo V, Brunetti O, Gnoni A, Cascinu S, Gasparini G, Lorusso V, et al. Angiogenesis in pancreatic ductal adenocarcinoma: a controversial issue. Oncotarget. 2016;7:58649–58. [DOI] [PubMed] [PMC]

24.

Huang Q, Duan L, Qian X, Fan J, Lv Z, Zhang X, et al. IL-17 promotes angiogenic factors IL-6, IL-8, and Vegf production via Stat1 in lung adenocarcinoma. Sci Rep. 2016;6:36551. Erratum in: Sci Rep. 2017;7:39566. [DOI] [PubMed] [PMC]

25.

Loncle C, Bonjoch L, Folch-Puy E, Lopez-Millan MB, Lac S, Molejon MI, et al. IL17 functions through the novel REG3β–JAK2–STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer. Cancer Res. 2015;75:4852–62. [DOI] [PubMed] [PMC]

26.

Wu X, Yang T, Liu X, Guo JN, Xie T, Ding Y, et al. IL-17 promotes tumor angiogenesis through Stat3 pathway mediated upregulation of VEGF in gastric cancer. Tumour Biol. 2016;37:5493–501. [DOI] [PubMed]

27.

Liu X, Zhou Z, Cheng Q, Wang H, Cao H, Xu Q, et al. Acceleration of pancreatic tumorigenesis under immunosuppressive microenvironment induced by Reg3g overexpression. Cell Death Dis. 2017;8:e3033. [DOI] [PubMed] [PMC]

28.

Hirano T. IL-6 in inflammation, autoimmunity and cancer. Int Immunol. 2021;33:127–48. [DOI] [PubMed] [PMC]

29.

Jung YY, Ko JH, Um JY, Chinnathambi A, Alharbi SA, Sethi G, et al. LDL cholesterol promotes the proliferation of prostate and pancreatic cancer cells by activating the STAT3 pathway. J Cell Physiol. 2021;236:5253–64. [DOI] [PubMed]

30.

Huber M, Brehm CU, Gress TM, Buchholz M, Alashkar Alhamwe B, von Strandmann EP, et al. The immune microenvironment in pancreatic cancer. Int J Mol Sci. 2020;21:7307. [DOI] [PubMed] [PMC]

31.

Hamarsheh S, Groß O, Brummer T, Zeiser R. Immune modulatory effects of oncogenic KRAS in cancer. Nat Commun. 2020;11:5439. [DOI] [PubMed] [PMC]

32.

Dosch AR, Singh S, Dai X, Mehra S, Silva IC, Bianchi A, et al. Targeting tumor–stromal IL6/STAT3 signaling through IL1 receptor inhibition in pancreatic cancer. Mol Cancer Ther. 2021;20:2280–90. [DOI] [PubMed] [PMC]

33.

Tandon M, Coudriet GM, Criscimanna A, Socorro M, Eliliwi M, Singhi AD, et al. Prolactin promotes fibrosis and pancreatic cancer progression. Cancer Res. 2019;79:5316–27. [DOI] [PubMed] [PMC]

34.

Dong Z, Santeford A, Ban N, Lee TJ, Smith C, Ornitz DM, et al. FGF2-induced STAT3 activation regulates pathologic neovascularization. Exp Eye Res. 2019;187:107775. [DOI] [PubMed] [PMC]

35.

He W, Wu J, Shi J, Huo YM, Dai W, Geng J, et al. IL22RA1/STAT3 signaling promotes stemness and tumorigenicity in pancreatic cancer. Cancer Res. 2018;78:3293–305. [DOI] [PubMed]

36.

Sasaki N, Hirano K, Shichi Y, Gomi F, Yoshimura H, Matsushita A, et al. Gp130-mediated STAT3 activation contributes to the aggressiveness of pancreatic cancer through H19 long non-coding RNA expression. Cancers (Basel). 2022;14:2055. [DOI] [PubMed] [PMC]

37.

Huang C, Xie K. Crosstalk of Sp1 and Stat3 signaling in pancreatic cancer pathogenesis. Cytokine Growth Factor Rev. 2012;23:25–35. [DOI] [PubMed] [PMC]

38.

Gibadulinova A, Oveckova I, Parkkila S, Pastorekova S, Pastorek J. Key promoter elements involved in transcriptional activation of the cancer-related gene coding for S100P calcium-binding protein. Oncol Rep. 2008;20:391–6. [PubMed]

39.

Park W, Chawla A, O’Reilly EM. Pancreatic cancer: a review. JAMA. 2021;326:851–62. Erratum in: JAMA. 2021;326:2081. [DOI] [PubMed] [PMC]

40.

Corcoran RB, Contino G, Deshpande V, Tzatsos A, Conrad C, Benes CH, et al. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 2011;71:5020–9. [DOI] [PubMed] [PMC]

41.

Xu Q, Briggs J, Park S, Niu G, Kortylewski M, Zhang S, et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene. 2005;24:5552–60. [DOI] [PubMed]

42.

Fan X, Fu H, Xie N, Guo H, Fu T, Shan Y. Inhibition of JAK2/STAT3 signaling pathway by panaxadiol limits the progression of pancreatic cancer. Aging (Albany NY). 2021;13:22830–42. [DOI] [PubMed] [PMC]

43.

Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H, et al. Keratinocyte‐specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J. 1999;18:4657–68. [DOI] [PubMed] [PMC]

44.

Silver DL, Naora H, Liu J, Cheng W, Montell DJ. Activated signal transducer and activator of transcription (STAT) 3: localization in focal adhesions and function in ovarian cancer cell motility. Cancer Res. 2004;64:3550–8. [DOI] [PubMed]

45.

Klemke L, Fehlau CF, Winkler N, Toboll F, Singh SK, Moll UM, et al. The gain-of-function p53 R248W mutant promotes migration by STAT3 deregulation in human pancreatic cancer cells. Front Oncol. 2021;11:642603. [DOI] [PubMed] [PMC]

46.

Levina VV, Nolen B, Su Y, Godwin AK, Fishman D, Liu J, et al. Biological significance of prolactin in gynecologic cancers. Cancer Res. 2009;69:5226–33. [DOI] [PubMed] [PMC]

47.

Safa AR. Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces. Cancer Drug Resist. 2022;5:850–72. [DOI] [PubMed] [PMC]

48.

Adhikari AS, Agarwal N, Iwakuma T. Metastatic potential of tumor-initiating cells in solid tumors. Front Biosci (Landmark Ed). 2011;16:1927–38. [DOI] [PubMed]

49.

Bhagwandin VJ, Shay JW. Pancreatic cancer stem cells: fact or fiction? Biochim Biophys Acta. 2009;1792:248–59. [DOI] [PubMed] [PMC]

50.

Bubin R, Uljanovs R, Strumfa I. Cancer stem cells in pancreatic ductal adenocarcinoma. Int J Mol Sci. 2023;24:7030. [DOI] [PubMed] [PMC]

51.

Nagaraju GP, Farran B, Luong T, El-Rayes BF. Understanding the molecular mechanisms that regulate pancreatic cancer stem cell formation, stemness and chemoresistance: a brief overview. Semin Cancer Biol. 2023;88:67–80. [DOI] [PubMed]

52.

Subramaniam D, Kaushik G, Dandawate P, Anant S. Targeting cancer stem cells for chemoprevention of pancreatic cancer. Curr Med Chem. 2018;25:2585–94. [DOI] [PubMed] [PMC]

53.

Subramaniam D, Ramalingam S, Houchen CW, Anant S. Cancer stem cells: a novel paradigm for cancer prevention and treatment. Mini Rev Med Chem. 2010;10:359–71. [DOI] [PubMed] [PMC]

54.

Valle-Mendiola A, Soto-Cruz I. Energy metabolism in cancer: the roles of STAT3 and STAT5 in the regulation of metabolism-related genes. Cancers (Basel). 2020;12:124. [DOI] [PubMed] [PMC]

55.

Li M, Jin R, Wang W, Zhang T, Sang J, Li N, et al. STAT3 regulates glycolysis via targeting hexokinase 2 in hepatocellular carcinoma cells. Oncotarget. 2017;8:24777–84. [DOI] [PubMed] [PMC]

56.

Yucel B, Altundağ Kara S, Cekmen MB, Ada S, Demircan Tan B. STAT3 mediated regulation of glucose metabolism in leukemia cells. Gene. 2022;809:146012. [DOI] [PubMed]

57.

Valle S, Alcalá S, Martin-Hijano L, Cabezas-Sáinz P, Navarro D, Muñoz ER, et al. Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells. Nat Commun. 2020;11:5265. [DOI] [PubMed] [PMC]

58.

Li YJ, Zhang C, Martincuks A, Herrmann A, Yu H. STAT proteins in cancer: orchestration of metabolism. Nat Rev Cancer. 2023;23:115–34. [DOI] [PubMed]

59.

Poznanski SM, Singh K, Ritchie TM, Aguiar JA, Fan IY, Portillo AL, et al. Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment. Cell Metab. 2021;33:1205–20.E5. [DOI] [PubMed]

60.

Wang Y, Shen Y, Wang S, Shen Q, Zhou X. The role of STAT3 in leading the crosstalk between human cancers and the immune system. Cancer Lett. 2018;415:117–28. [DOI] [PubMed] [PMC]

61.

Chang Q, Bournazou E, Sansone P, Berishaj M, Gao SP, Daly L, et al. The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia. 2013;15:848–62. [DOI] [PubMed] [PMC]

62.

Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007;7:41–51. [DOI] [PubMed]

63.

Zou S, Tong Q, Liu B, Huang W, Tian Y, Fu X. Targeting STAT3 in cancer immunotherapy. Mol Cancer. 2020;19:145. [DOI] [PubMed] [PMC]

64.

Mucileanu A, Chira R, Mircea PA. PD-1/PD-L1 expression in pancreatic cancer and its implication in novel therapies. Med Pharm Rep. 2021;94:402–10. [DOI] [PubMed] [PMC]

65.

Kythreotou A, Siddique A, Mauri FA, Bower M, Pinato DJ. PD-L1. J Clin Pathol. 2018;71:189–94. [DOI] [PubMed]

66.

Hu G, He N, Cai C, Cai F, Fan P, Zheng Z, et al. HDAC3 modulates cancer immunity via increasing PD-L1 expression in pancreatic cancer. Pancreatology. 2019;19:383–9. [DOI] [PubMed]

67.

Biffi G, Oni TE, Spielman B, Hao Y, Elyada E, Park Y, et al. IL1-induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 2019;9:282–301. [DOI] [PubMed] [PMC]

68.

Velez-Delgado A, Donahue KL, Brown KL, Du W, Irizarry-Negron V, Menjivar RE, et al. Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming. Cell Mol Gastroenterol Hepatol. 2022;13:1673–99. [DOI] [PubMed] [PMC]

69.

Bekaii-Saab T, Okusaka T, Goldstein D, Oh DY, Ueno M, Ioka T, et al. Napabucasin plus nab-paclitaxel with gemcitabine versus nab-paclitaxel with gemcitabine in previously untreated metastatic pancreatic adenocarcinoma: an adaptive multicentre, randomised, open-label, phase 3, superiority trial. EClinicalMedicine. 2023;58:101897. [DOI] [PubMed] [PMC]

70.

Lin TS, Ruppert AS, Johnson AJ, Fischer B, Heerema NA, Andritsos LA, et al. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol. 2009;27:6012–8. [DOI] [PubMed] [PMC]

71.

Chen H, Bian A, Yang LF, Yin X, Wang J, Ti C, et al. Targeting STAT3 by a small molecule suppresses pancreatic cancer progression. Oncogene. 2021;40:1440–57. [DOI] [PubMed] [PMC]

72.

Zheng Q, Dong H, Mo J, Zhang Y, Huang J, Ouyang S, et al. A novel STAT3 inhibitor W2014-S regresses human non-small cell lung cancer xenografts and sensitizes EGFR-TKI acquired resistance. Theranostics. 2021;11:824–40. [DOI] [PubMed] [PMC]

73.

Tintelnot J, Xu Y, Lesker TR, Schönlein M, Konczalla L, Giannou AD, et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature. 2023;615:168–74. [DOI] [PubMed] [PMC]

74.

Ntala C, Debernardi S, Feakins RM, Crnogorac-Jurcevic T. Demographic, clinical, and pathological features of early onset pancreatic cancer patients. BMC Gastroenterol. 2018;18:139. [DOI] [PubMed] [PMC]