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Cited by 228Cytokine Signaling Pathways and InteractionsHepatocellular Carcinoma Treatment and PrognosisLiver physiology and pathology

IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma

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Xu, Junnv, Lin, Haifeng, Wu, Gang, Zhu, Mingyue, Li, Mengsen·2021·Frontiers in Oncology
DOI 10.3389/fonc.2021.760971PMC PMC8714735
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Abstract

Hepatocellular carcinoma (HCC) is a common malignant tumor of which the occurrence and development, the tumorigenicity of HCC is involving in multistep and multifactor interactions. Interleukin-6 (IL-6), a multifunctional inflammatory cytokine, has increased expression in HCC patients and is closely related to the occurrence of HCC and prognosis. IL-6 plays a role by binding to the IL-6 receptor (IL-6R) and then triggering the Janus kinase (JAK) associated with the receptor, stimulating phosphorylation and activating signal transducer and activator of transcription 3 (STAT3) to initiate downstream signals, participating in the processes of anti-apoptosis, angiogenesis, proliferation, invasion, metastasis, and drug resistance of cancer cells. IL-6/STAT3 signal axes elicit an immunosuppressive in tumor microenvironment, it is important to therapy HCC by blocking the IL-6/STAT3 signaling pathway. Recent, some inhibitors of IL-6/STAT3 have been development, such as S31-201 or IL-6 neutralizing monoclonal antibody (IL-6 mAb), Madindoline A (Inhibits the dimerization of IL-6/IL-6R/gpl30 trimeric complexes), C188-9 and Curcumin (Inhibits STAT3 phosphorylation), etc. for treatment of cancers. Overall, consideration of the IL-6/STAT3 signaling pathway, and its role in the carcinogenesis and progression of HCC will contribute to the development of potential drugs for targeting treatment of liver cancer.

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  1. [1]Attia YM Tawfiq RA Ali AA Elmazar MM. The FXR Agonist, Obeticholic Acid, Suppresses HCC Proliferation & Metastasis: Role of IL-6/STAT3 Signalling Pathway. Sci Rep (2017) 7(1): 12502. doi: 10.1038/s41598-017-12629-4 28970500 PMC5624958 · DOI
  2. [2]Yang Y Wang W Chang H Han Z Yu X Zhang T. Reciprocal Regulation of miR-206 and IL-6/STAT3 Pathway Mediates IL6-Induced Gefitinib Resistance in EGFR-Mutant Lung Cancer Cells. J Cell Mol Med (2019) 23: 7331–41. doi: 10.1111/jcmm.14592 PMC6815809 31507089 · DOI
  3. [3]Chen J Huang X Li N Liu B Ma Z Ling J. Narasin Inhibits Tumor Metastasis and Growth of ERalphapositive Breast Cancer Cells by Inactivation of the TGFbeta/SMAD3 and IL6/STAT3 Signaling Pathways. Mol Med Rep (2020) 22: 5113–24. doi: 10.3892/mmr.2020.11624 PMC7646975 33174044 · DOI
  4. [4]Hao Y Yan Z Zhang A Hu S Wang N Luo XG. IL-6/STAT3 Mediates the HPV18 E6/E7 Stimulated Upregulation of MALAT1 Gene in Cervical Cancer HeLa Cells. Virus Res (2020) 281: 197907. doi: 10.1016/j.virusres.2020.197907 32113834 · DOI
  5. [5]Tang X Ding Q Chen C Chen F Zhou X Hong CJ. Micheliolide Inhibits Gastric Cancer Growth In Vitro and In Vivo via Blockade of the IL-6/STAT3 Pathway. Pharmazie (2019) 74: 175–78. doi: 10.1691/ph.2019.8816 30961685 · DOI
  6. [6]Siegel RL Miller KD Fuchs HE Jemal A. Cancer Statistics, 2021. CA Cancer J Clin (2021) 71: 7– 33. doi: 10.3322/caac.21654 33433946 · DOI · Paper page
  7. [8]Dai CY Tsai YS Chou WW Liu T Huang CF Wang SC. The IL-6/STAT3 pathway upregulates microRNA-125b Expression in Hepatitis C Virus Infection. Oncotarget (2018) 9: 11291–302. doi: 10.18632/oncotarget.24129 PMC5834265 29541414 · DOI
  8. [9]Qin SK Li Q Ming Xu J Liang J Cheng Y Fan Y. Icaritin-Induced Immunomodulatory Efficacy in Advanced Hepatitis B Virus-Related Hepatocellular Carcinoma: Immunodynamic Biomarkers and Overall Survival. Cancer Sci (2020) 111: 4218–31. doi: 10.1111/cas.14641 PMC7648021 32889778 · DOI
  9. [10]Song J Zhang X Ge Q Yuan C Chu L Liang HF. CRISPR/Cas9-Mediated Knockout of HBsAg Inhibits Proliferation and Tumorigenicity of HBV-Positive Hepatocellular Carcinoma Cells. J Cell Biochem (2018) 119: 8419–31. doi: 10.1002/jcb.27050 PMC6221038 29904948 · DOI
  10. [11]Forner A Reig M Bruix J. Hepatocellular Carcinoma. Lancet (2018) 391: 1301–14. doi: 10.1016/S0140-6736(18)30010-2 29307467 · DOI
  11. [12]Liu Y Fuchs J Li C Lin J. IL-6, a Risk Factor for Hepatocellular Carcinoma: FLLL32 Inhibits IL-6-Induced STAT3 Phosphorylation in Human Hepatocellular Cancer Cells. Cell Cycle (2010) 9: 3423–27. doi: 10.4161/cc.9.17.12946 20818158 · DOI
  12. [13]Giraldez MD Carneros D Garbers C Rose-John S Bustos M. New insights into IL-6 Family Cytokines in Metabolism, Hepatology and Gastroenterology. Nat Rev Gastroenterol Hepatol (2021) 18(11): 787– 803. doi: 10.1038/s41575-021-00473-x 34211157 · DOI · Paper page
  13. [14]Pan T Zhang F Li F Gao X Li Z Li X. Shikonin Blocks Human Lung Adenocarcinoma Cell Migration and Invasion in the Inflammatory Microenvironment via the IL-6/STAT3 signaling Pathway. Oncol Rep (2020) 44: 1049–63. doi: 10.3892/or.2020.7683 PMC7388308 32705271 · DOI
  14. [15]Won C Kim BH Yi EH Choi KJ Kim EK Jeong JM. Signal transducer and Activator of Transcription 3-Mediated CD133 Up-Regulation Contributes to Promotion of Hepatocellular Carcinoma. Hepatology (2015) 62: 1160–73. doi: 10.1002/hep.27968 PMC5049669 26154152 · DOI
  15. [16]Wu J Zhang J Shen B Yin K Xu J Gao W. Long Noncoding RNA Lnctcf7, Induced by IL-6/STAT3 transactivation, Promotes Hepatocellular Carcinoma Aggressiveness Through Epithelial-Mesenchymal Transition. J Exp Clin Cancer Res (2015) 34: 116. doi: 10.1186/s13046-015-0229-3 26452542 PMC4600266 · DOI
  16. [17]Kao JT Feng CL Yu CJ Tsai SM Hsu PN Chen YL. IL-6, Through P-STAT3 Rather Than P-STAT1, Activates Hepatocarcinogenesis and Affects Survival of Hepatocellular Carcinoma Patients: A Cohort Study. BMC Gastroenterol (2015) 15: 50. doi: 10.1186/s12876-015-0283-5 25908103 PMC4424593 · DOI
  17. [18]Yin Z Ma T Lin Y Lu X Zhang C Chen S. IL-6/STAT3 Pathway Intermediates M1/M2 Macrophage Polarization During the Development of Hepatocellular Carcinoma. J Cell Biochem (2018) 119: 9419–32. doi: 10.1002/jcb.27259 30015355 · DOI
  18. [19]Iwahasi S Rui F Morine Y Yamada S Saito YU Ikemoto T. Hepatic Stellate Cells Contribute to the Tumor Malignancy of Hepatocellular Carcinoma Through the IL-6 Pathway. Anticancer Res (2020) 40: 743–49. doi: 10.21873/anticanres.14005 32014916 · DOI
  19. [20]Kishimoto T. IL-6: From its Discovery to Clinical Applications. Int Immunol (2010) 22: 347–52. doi: 10.1093/intimm/dxq030 20410258 · DOI · Paper page
  20. [21]Tanaka T Kishimoto T. The Biology and Medical Implications of Interleukin-6. Cancer Immunol Res (2014) 2: 288–94. doi: 10.1158/2326-6066.CIR-14-0022 24764575 · DOI
  21. [22]Rincon M Irvin CG. Role of IL-6 in Asthma and Other Inflammatory /Pulmonary Diseases. Int J Biol Sci (2012) 8: 1281–90. doi: 10.7150/ijbs.4874 PMC3491451 23136556 · DOI
  22. [23]Baran P Hansen S Waetzig GH Akbarzadeh M Lamertz L Huber HJ. The Balance of Interleukin (IL)-6, IL-6.Soluble IL-6 Receptor (sIL-6R), and IL-6.sIL-6R.Sgp130 Complexes Allows Simultaneous Classic and Trans-Signaling. J Biol Chem (2018) 293: 6762–75. doi: 10.1074/jbc.RA117.001163 PMC5936821 29559558 · DOI · Paper page
  23. [24]Prenissl N Lokau J Rose-John S Haybaeck J Garbers C. Therapeutic Blockade of the Interleukin-6 Receptor (IL-6R) Allows sIL-6R Generation by Proteolytic Cleavage. Cytokine (2019) 114: 1– 05. doi: 10.1016/j.cyto.2018.11.023 30557809 · DOI
  24. [25]Rose-John S. Interleukin-6 Family Cytokines. Cold Spring Harb Perspect Biol (2018) 10: a028415. doi: 10.1101/cshperspect.a028415 28620096 PMC5793756 · DOI
  25. [27]Miklossy G Hilliard TS Turkson J. Therapeutic Modulators of STAT Signalling for Human Diseases. Nat Rev Drug Discov (2013) 12: 611–29. doi: 10.1038/nrd4088 PMC4038293 23903221 · DOI
  26. [28]Shi W Inoue M Minami M Takeda K Matsumoto M Matsuda Y. The Genomic Structure and Chromosomal Localization of the Mouse STAT3 Gene. Int Immunol (1996) 8(8): 1205–11. doi: 10.1093/intimm/8.8.1205 8918689 · DOI
  27. [29]Johnson DE O'Keefe RA Grandis JR. Targeting the IL-6/JAK/STAT3 Signalling Axis in Cancer. Nat Rev Clin Oncol (2018) 15: 234–48. doi: 10.1038/nrclinonc.2018.8 PMC5858971 29405201 · DOI · Paper page
  28. [30]Fan Y Mao R Yang J. NF-kappaB and STAT3 Signaling Pathways Collaboratively Link Inflammation to Cancer. Protein Cell (2013) 4: 176–85. doi: 10.1007/s13238-013-2084-3 PMC4875500 23483479 · DOI
  29. [31]Abroun S Saki N Ahmadvand M Asghari F Salari F Rahim F. STATs: An Old Story, Yet Mesmerizing. Cell J (2015) 17: 395– 411. doi: 10.22074/cellj.2015.1 26464811 PMC4601860 · DOI
  30. [32]Wake MS Watson CJ. STAT3 the Oncogene - Still Eluding Therapy? FEBS J (2015) 282: 2600–11. doi: 10.1111/febs.13285 25825152 · DOI
  31. [33]Zhang X Sun Y Pireddu R Yang H Urlam MK Lawrence HR. A Novel Inhibitor of STAT3 Homodimerization Selectively Suppresses STAT3 Activity and Malignant Transformation. Cancer Res (2013) 73: 1922–33. doi: 10.1158/0008-5472.CAN-12-3175 PMC4030628 23322008 · DOI
  32. [34]Liu C Liu H Chen J. The Role of SOCS in the Development of Tumors. Zhongguo Fei Ai Za Zhi (2016) 19: 620–25. doi: 10.3779/j.issn.1009-3419.2016.09.11 PMC5972954 27666555 · DOI
  33. [35]Inagaki-Ohara K Kondo T Ito M Yoshimura A. SOCS. Inflammation, and Cancer. JAKSTAT (2013) 2: e24053. doi: 10.4161/jkst.24053 24069550 PMC3772102 · DOI
  34. [36]Xie J Wang M Cheng A Jia R Zhu D Liu M. The Role of SOCS Proteins in the Development of Virus-Induced Hepatocellular Carcinoma. Virol J (2021) 18: 74. doi: 10.1186/s12985-021-01544-w 33849568 PMC8045357 · DOI
  35. [37]Chu PY Yeh CM Hsu NC Chang YS Chang JG Yeh KT. Epigenetic Alteration of the SOCS1 Gene in Hepatocellular Carcinoma. Swiss Med Wkly (2010) 140: w13065. doi: 10.4414/smw.2010.13065 20648401 · DOI
  36. [38]Quintas-Cardama A Verstovsek S. Molecular Pathways: Jak/STAT Pathway: Mutations, Inhibitors, and Resistance. Clin Cancer Res (2013) 19: 1933–40. doi: 10.1158/1078-0432.CCR-12-0284 PMC5021219 23406773 · DOI
  37. [39]Niu GJ Xu JD Yuan WJ Sun JJ Yang MC He ZH. Protein Inhibitor of Activated STAT (PIAS) Negatively Regulates the JAK/STAT Pathway by Inhibiting STAT Phosphorylation and Translocation. Front Immunol (2018) 9: 2392. doi: 10.3389/fimmu.2018.02392 30416501 PMC6212522 · DOI
  38. [41]Bard-Chapeau EA Li S Ding J Zhang SS Zhu HH Princen F. Ptpn11/Shp2 Acts as a Tumor Suppressor in Hepatocellular Carcinogenesis. Cancer Cell (2011) 19: 629–39. doi: 10.1016/j.ccr.2011.03.023 PMC3098128 21575863 · DOI · Paper page
  39. [42]Fan LC Shiau CW Tai WT Hung MH Chu PY Hsieh FS. SHP-1 Is a Negative Regulator of Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma. Oncogene (2015) 34: 5252–63. doi: 10.1038/onc.2014.445 25619838 · DOI
  40. [43]Fahmi A Smart N Punn A Jabr R Marber M Heads R. P42/P44-MAPK and PI3K are Sufficient for IL-6 Family Cytokines/Gp130 to Signal to Hypertrophy and Survival in Cardiomyocytes in the Absence of JAK/STAT Activation. Cell Signal (2013) 25: 898– 909. doi: 10.1016/j.cellsig.2012.12.008 23268184 PMC3627957 · DOI
  41. [44]Herranz H Hong X Hung NT Voorhoeve PM Cohen SM. Oncogenic Cooperation Between SOCS Family Proteins and EGFR Identified Using a Drosophila Epithelial Transformation Model. Genes Dev (2012) 26: 1602–11. doi: 10.1101/gad.192021.112 PMC3404387 22802531 · DOI
  42. [45]Coskun M Salem M Pedersen J Nielsen OH. Involvement of JAK/STAT Signaling in the Pathogenesis of Inflammatory Bowel Disease. Pharmacol Res (2013) 76: 1– 08. doi: 10.1016/j.phrs.2013.06.007 23827161 · DOI
  43. [46]Slomiany BL Slomiany A. Involvement of P38 MAPK-Dependent Activator Protein (AP-1) Activation in Modulation of Gastric Mucosal Inflammatory Responses to Helicobacter Pylori by Ghrelin. Inflammopharmacology (2013) 21: 67– 78. doi: 10.1007/s10787-012-0141-9 22669511 · DOI
  44. [48]Mackillop WJ Ciampi A Till JE Buick RN. A Stem Cell Model of Human Tumor Growth: Implications for Tumor Cell Clonogenic Assays. J Natl Cancer Inst (1983) 70: 9– 16. doi: 10.1016/S0022-5347(17)51493-7 6571928 · DOI
  45. [49]Liu YC Yeh CT Lin KH. Cancer Stem Cell Functions in Hepatocellular Carcinoma and Comprehensive Therapeutic Strategies. Cells-Basel (2020) 9: 1331. doi: 10.3390/cells9061331 PMC7349579 32466488 · DOI
  46. [50]Ji J Wang XW. Clinical Implications of Cancer Stem Cell Biology in Hepatocellular Carcinoma. Semin Oncol (2012) 39: 461–72. doi: 10.1053/j.seminoncol.2012.05.011 PMC3409471 22846863 · DOI
  47. [51]Wang X Sun W Shen W Xia M Chen C Xiang D. Long Non-Coding RNA DILC Regulates Liver Cancer Stem Cells via IL-6/STAT3 Axis. J Hepatol (2016) 64: 1283–94. doi: 10.1016/j.jhep.2016.01.019 26812074 · DOI
  48. [52]Ghoshal S Fuchs BC Tanabe KK. STAT3 Is a Key Transcriptional Regulator of Cancer Stem Cell Marker CD133 in HCC. Hepatobiliary Surg Nutr (2016) 5: 201–03. doi: 10.21037/hbsn.2016.03.02 PMC4876240 27275460 · DOI
  49. [53]Wan S Zhao E Kryczek I Vatan L Sadovskaya A Ludema G. Tumor-Associated Macrophages Produce Interleukin 6 and Signal via STAT3 to Promote Expansion of Human Hepatocellular Carcinoma Stem Cells. Gastroenterology (2014) 147: 1393–404. doi: 10.1053/j.gastro.2014.08.039 PMC4253315 25181692 · DOI
  50. [54]Li Y Chen G Han Z Cheng H Qiao L Li Y. IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells. Onco Targets Ther (2020) 13: 9721–30. doi: 10.2147/OTT.S262089 PMC7533247 33061451 · DOI
  51. [55]Ahodantin J Lekbaby B Bou NM Soussan P Kremsdorf D. Hepatitis B Virus X Protein Enhances the Development of Liver Fibrosis and the Expression of Genes Associated With Epithelial-Mesenchymal Transitions and Tumor Progenitor Cells. Carcinogenesis (2020) 41: 358–67. doi: 10.1093/carcin/bgz109 31175830 · DOI
  52. [56]Sasaki R Devhare P Ray RB Ray R. Hepatitis C Virus-Induced Tumor-Initiating Cancer Stem-Like Cells Activate Stromal Fibroblasts in a Xenograft Tumor Model. Hepatology (2017) 66: 1766–78. doi: 10.1002/hep.29346 PMC5696059 28664988 · DOI
  53. [57]Chen CL Tsukamoto H Machida K. Oncogenic Signaling Pathways and Origins of Tumor-Initiating Stem-Like Cells of Hepatocellular Carcinomas Induced by Hepatitis C Virus, Alcohol and/or Obesity. Hepatol Int (2014) 8: 330–38. doi: 10.1007/s12072-014-9545-5 PMC10560513 26202636 · DOI
  54. [58]Zhou X Yang F Yang Y Hu Y Liu W Huang C. HBV Facilitated Hepatocellular Carcinoma Cells Proliferation by Up-Regulating Angiogenin Expression Through IL-6. Cell Physiol Biochem (2018) 46: 461–70. doi: 10.1159/000488614 29614505 · DOI
  55. [59]Quetier I Brezillon N Duriez M Massinet H Giang E Ahodantin J. Hepatitis B Virus HBx Protein Impairs Liver Regeneration Through Enhanced Expression of IL-6 in Transgenic Mice. J Hepatol (2013) 59: 285–91. doi: 10.1016/j.jhep.2013.03.021 23542345 · DOI
  56. [60]Hu ZG Zhang S Chen YB Cao W Zhou ZY Zhang JN. DTNA Promotes HBV-Induced Hepatocellular Carcinoma Progression by Activating STAT3 and Regulating TGFbeta1 and P53 Signaling. Life Sci (2020) 258: 118029. doi: 10.1016/j.lfs.2020.118029 32619495 · DOI
  57. [61]Pham TH Park HM Kim J Hong JT Yoon DY. STAT3 and P53: Dual Target for Cancer Therapy. Biomedicines (2020) 8: 637. doi: 10.3390/biomedicines8120637 PMC7767392 33371351 · DOI
  58. [62]Chen T Dai X Dai J Ding C Zhang Z Lin Z. AFP Promotes HCC Progression by Suppressing the HuR-Mediated Fas/FADD Apoptotic Pathway. Cell Death Dis (2020) 11: 822. doi: 10.1038/s41419-020-03030-7 33009373 PMC7532541 · DOI
  59. [63]Zheng Y Zhu M Li M. Effects of Alpha-Fetoprotein on the Occurrence and Progression of Hepatocellular Carcinoma. J Cancer Res Clin Oncol (2020) 146: 2439–46. doi: 10.1007/s00432-020-03331-6 PMC11804406 32725355 · DOI
  60. [64]Wang S Zhu M Wang Q Hou Y Li L Weng H. Alpha-Fetoprotein Inhibits Autophagy to Promote Malignant Behaviour in Hepatocellular Carcinoma Cells by Activating PI3K/AKT/mTOR Signalling. Cell Death Dis (2018) 9: 1027. doi: 10.1038/s41419-018-1036-5 30301886 PMC6177398 · DOI
  61. [65]Zhu M Li W Lu Y Dong X Lin B Chen Y. HBx Drives Alpha Fetoprotein Expression to Promote Initiation of Liver Cancer Stem Cells Through Activating PI3K/AKT Signal Pathway. Int J Cancer (2017) 140: 1346–55. doi: 10.1002/ijc.30553 27925189 · DOI
  62. [66]Docta RY Ferronha T Sanderson JP Weissensteiner T Pope GR Bennett AD. Tuning T-Cell Receptor Affinity to Optimize Clinical Risk-Benefit When Targeting Alpha-Fetoprotein-Positive Liver Cancer. Hepatology (2019) 69: 2061–75. doi: 10.1002/hep.30477 PMC6593660 30561769 · DOI
  63. [67]Ogden SK Lee KC Barton MC. Hepatitis B Viral Transactivator HBx Alleviates P53-Mediated Repression of Alpha-Fetoprotein Gene Expression. J Biol Chem (2000) 275: 27806–14. doi: 10.1074/jbc.M004449200 10842185 · DOI
  64. [68]Lee J Fenton BM Koch CJ Frelinger JG Lord EM. Interleukin 2 Expression by Tumor Cells Alters Both the Immune Response and the Tumor Microenvironment. Cancer Res (1998) 58(7): 1478–85. 9537251
  65. [69]Baird RD Linossi C Middleton M Lord S Harris A Rodón J. First-In-Human Phase I Study of MP0250, a First-in-Class DARP in Drug Candidate Targeting VEGF and HGF, in Patients With Advanced Solid Tumors. J Clin Oncol (2021) 39(2): 145–54. doi: 10.1200/JCO.20.00596 PMC8196087 33301375 · DOI
  66. [70]Chou J Shahi P Werb Z. microRNA-Mediated Regulation of the Tumor Microenvironment. Cell Cycle (2013) 12: 3262–71. doi: 10.4161/cc.26087 PMC3885637 24036551 · DOI
  67. [71]Wu M Swartz MA. Modeling Tumor Microenvironments In Vitro. J Biomech Eng (2014) 136: 21011. doi: 10.1115/1.4026447 PMC4023667 24402507 · DOI
  68. [72]Bournazou E Bromberg J. Targeting the Tumor Microenvironment: JAK-STAT3 Signaling. JAKSTAT (2013) 2: e23828. doi: 10.4161/jkst.23828 24058812 PMC3710325 · DOI
  69. [73]Zheng X Xu M Yao B Wang C Jia Y Liu Q. IL-6/STAT3 Axis Initiated CAFs via Up-Regulating TIMP-1 Which was Attenuated by Acetylation of STAT3 Induced by PCAF in HCC Microenvironment. Cell Signal (2016) 28: 1314–24. doi: 10.1016/j.cellsig.2016.06.009 27297362 · DOI
  70. [74]Subramaniam A Shanmugam MK Ong TH Li F Perumal E Chen L. Emodin Inhibits Growth and Induces Apoptosis in an Orthotopic Hepatocellular Carcinoma Model by Blocking Activation of STAT3. Br J Pharmacol (2013) 170: 807–21. doi: 10.1111/bph.12302 PMC3799595 23848338 · DOI
  71. [75]Zhao H Guo Y Li S Han R Ying J Zhu H. A Novel Anti-Cancer Agent Icaritin Suppresses Hepatocellular Carcinoma Initiation and Malignant Growth Through the IL-6/Jak2/Stat3 Pathway. Oncotarget (2015) 6: 31927–43. doi: 10.18632/oncotarget.5578 PMC4741651 26376676 · DOI
  72. [76]Kim B Park B. Saffron Carotenoids Inhibit STAT3 Activation and Promote Apoptotic Progression in IL-6-Stimulated Liver Cancer Cells. Oncol Rep (2018) 39: 1883–91. doi: 10.3892/or.2018.6232 29393468 · DOI
  73. [77]Siddiqui WA Ahad A Ahsan H. The Mystery of BCL2 Family: Bcl-2 Proteins and Apoptosis: An Update. Arch Toxicol (2015) 89: 289– 317. doi: 10.1007/s00204-014-1448-7 25618543 · DOI
  74. [78]He G Karin M. NF-kappaB and STAT3 - Key Players in Liver Inflammation and Cancer. Cell Res (2011) 21: 159–68. doi: 10.1038/cr.2010.183 PMC3193410 21187858 · DOI
  75. [79]Yamada S Okumura N Wei L Fuchs BC Fujii T Sugimoto H. Epithelial to Mesenchymal Transition is Associated With Shorter Disease-Free Survival in Hepatocellular Carcinoma. Ann Surg Oncol (2014) 21: 3882–90. doi: 10.1245/s10434-014-3779-2 24833103 · DOI
  76. [80]Fossey SL Bear MD Kisseberth WC Pennell M London CA. Oncostatin M Promotes STAT3 Activation, VEGF Production, and Invasion in Osteosarcoma Cell Lines. BMC Cancer (2011) 11: 125. doi: 10.1186/1471-2407-11-125 21481226 PMC3079692 · DOI
  77. [81]Piccioni F Fiore E Bayo J Atorrasagasti C Peixoto E Rizzo M. 4-Methylumbelliferone Inhibits Hepatocellular Carcinoma Growth by Decreasing IL-6 Production and Angiogenesis. Glycobiology (2015) 25: 825–35. doi: 10.1093/glycob/cwv023 25882295 · DOI
  78. [82]Du P Cao H Wu HR Zhu BS Wang HW Gu CW. Blocking Bcl-2 Leads to Autophagy Activation and Cell Death of the HEPG2 Liver Cancer Cell Line. Asian Pac J Cancer Prev (2013) 14: 5849–54. doi: 10.7314/apjcp.2013.14.10.5849 24289588 · DOI
  79. [83]Wang ST Huang SW Liu KT Lee TY Shieh JJ Wu CY. Atorvastatin-Induced Senescence of Hepatocellular Carcinoma is Mediated by Downregulation of hTERT Through the Suppression of the IL-6/STAT3 pathway. Cell Death Discov (2020) 6: 17. doi: 10.1038/s41420-020-0252-9 32257389 PMC7105491 · DOI
  80. [84]Chen R Cui J Xu C Xue T Guo K Gao D. The Significance of MMP-9 Over MMP-2 in HCC Invasiveness and Recurrence of Hepatocellular Carcinoma After Curative Resection. Ann Surg Oncol (2012) 19(Suppl 3): S375–84. doi: 10.1245/s10434-011-1836-7 21681378 · DOI
  81. [85]Zhou L Wang DS Li QJ Sun W Zhang Y Dou KF. Downregulation of the Notch Signaling Pathway Inhibits Hepatocellular Carcinoma Cell Invasion by Inactivation of Matrix Metalloproteinase-2 and -9 and Vascular Endothelial Growth Factor. Oncol Rep (2012) 28: 874–82. doi: 10.3892/or.2012.1880 22736202 · DOI
  82. [86]Song X Yang W Wu C Han Y Lu Y. USP9X Promotes the Proliferation, Invasion and Metastasis of Liver Cancer Cells Through Regulating the JAK2/STAT3 Signaling. Oncol Lett (2020) 20: 2897–905. doi: 10.3892/ol.2020.11824 PMC7400992 32782606 · DOI
  83. [87]Castellanos JA Merchant NB Nagathihalli NS. Emerging Targets in Pancreatic Cancer: Epithelial-Mesenchymal Transition and Cancer Stem Cells. Onco Targets Ther (2013) 6: 1261–67. doi: 10.2147/OTT.S34670 PMC3775701 24049451 · DOI
  84. [88]Cho KH Jeong KJ Shin SC Kang J Park CG Lee HY. STAT3 Mediates TGF-Beta1-Induced TWIST1 Expression and Prostate Cancer Invasion. Cancer Lett (2013) 336: 167–73. doi: 10.1016/j.canlet.2013.04.024 23623921 · DOI
  85. [89]Zhang CH Xu GL Jia WD Li JS Ma JL Ren WH. Activation of STAT3 Signal Pathway Correlates With Twist and E-Cadherin Expression in Hepatocellular Carcinoma and Their Clinical Significance. J Surg Res (2012) 174: 120–29. doi: 10.1016/j.jss.2010.10.030 21316706 · DOI
  86. [90]Kitamura H Ohno Y Toyoshima Y Ohtake J Homma S Kawamura H. Interleukin-6/STAT3 Signaling as a Promising Target to Improve the Efficacy of Cancer Immunotherapy. Cancer Sci (2017) 108: 1947–52. doi: 10.1111/cas.13332 PMC5623748 28749573 · DOI · Paper page
  87. [91]Peng M Huang B Zhang Q Fu S Wang D Cheng X. Embelin Inhibits Pancreatic Cancer Progression by Directly Inducing Cancer Cell Apoptosis and Indirectly Restricting IL-6 Associated Inflammatory and Immune Suppressive Cells. Cancer Lett (2014) 354: 407–16. doi: 10.1016/j.canlet.2014.08.011 25128650 · DOI
  88. [92]Shang A Wang W Gu C Chen C Zeng B Yang Y. Long non-Coding RNA HOTTIP Enhances IL-6 Expression to Potentiate Immune Escape of Ovarian Cancer Cells by Upregulating the Expression of PD-L1 in Neutrophils. J Exp Clin Cancer Res (2019) 38: 411. doi: 10.1186/s13046-019-1394-6 31533774 PMC6751824 · DOI
  89. [93]Liu H Shen J Lu K. IL-6 and PD-L1 Blockade Combination Inhibits Hepatocellular Carcinoma Cancer Development in Mouse Model. Biochem Biophys Res Commun (2017) 486: 239–44. doi: 10.1016/j.bbrc.2017.02.128 28254435 · DOI
  90. [94]Ghandadi M Sahebkar A. Interleukin-6: A Critical Cytokine in Cancer Multidrug Resistance. Curr Pharm Des (2016) 22: 518–26. doi: 10.2174/1381612822666151124234417 26601970 · DOI
  91. [95]Xie Y Zhong DW. AEG-1 is Associated With Hypoxia-Induced Hepatocellular Carcinoma Chemoresistance via Regulating PI3K/AKT/HIF-1alpha/MDR-1 Pathway. Excli J (2016) 15: 745–57. doi: 10.17179/excli2016-694 PMC5318678 28337106 · DOI
  92. [96]Yang J Wang J Luo J. Decreased IL-6 Induces Sensitivity of Hepatocellular Carcinoma Cells to Sorafenib. Pathol Res Pract (2019) 215: 152565. doi: 10.1016/j.prp.2019.152565 31387809 · DOI
  93. [97]Saleh AZ Greenman KL Billings S Van Vranken DL Krolewski JJ. Binding of Madindoline A to the Extracellular Domain of Gp130. Biochemistry (2005) 44: 10822–7. doi: 10.1021/bi050439+ 16086584 · DOI
  94. [98]Chen R Chen B. Siltuximab (CNTO 328): A Promising Option for Human Malignancies. Drug Des Devel Ther (2015) 9: 3455–8. doi: 10.2147/DDDT.S86438 PMC4494175 26170629 · DOI · Paper page
  95. [99]Rovin BH van Vollenhoven RF Aranow C Wagner C Gordon R Zhuang Y. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Treatment With Sirukumab (CNTO 136) in Patients With Active Lupus Nephritis. Arthritis Rheumatol (2016) 68: 2174–83. doi: 10.1002/art.39722 PMC5129491 27110697 · DOI
  96. [100]Bayliss TJ Smith JT Schuster M Dragnev KH Rigas JR. A Humanized Anti-IL-6 Antibody (ALD518) in Non-Small Cell Lung Cancer. Expert Opin Biol Ther (2011) 11: 1663–8. doi: 10.1517/14712598.2011.627850 21995322 · DOI
  97. [101]Kampan NC Xiang SD McNally OM Stephens AN Quinn MA Plebanski M. Immunotherapeutic Interleukin-6 or Interleukin-6 Receptor Blockade in Cancer: Challenges and Opportunities. Curr Med Chem (2018) 25(36): 4785–806. doi: 10.2174/0929867324666170712160621.PMID:28707587 28707587 · DOI
  98. [102]Dijkgraaf EM Santegoets SJ Reyners AK Goedemans R Wouters MC Kenter GG. A Phase I Trial Combining Carboplatin/Doxorubicin With Tocilizumab, an Anti-IL-6R Monoclonal Antibody, and Interferon-Alpha2b in Patients With Recurrent Epithelial Ovarian Cancer. Ann Oncol (2015) 26: 2141–9. doi: 10.1093/annonc/mdv309 26216383 · DOI
  99. [103]Campo S Serlupi-Crescenzi O Arseni B Rossi S Saggio I Salone B. Comparative Activity of Sant7 and Anti-IL-6, IL-6R Monoclonal Antibodies in a Murine Model of B-Cell Lymphoma. Cytokine (2005) 31(5): 368–74. doi: 10.1016/j.cyto.2005.06.006 16061391 · DOI
  100. [104]Oguro T Ishibashi K Sugino T Hashimoto K Tomita S Takahashi N. Humanised Antihuman IL-6R Antibody With Interferon Inhibits Renal Cell Carcinoma Cell Growth In Vitro and In Vivo Through Suppressed SOCS3 Expression. Eur J Cancer (2013) 49: 1715–24. doi: 10.1016/j.ejca.2012.11.038 23274199 · DOI
  101. [105]Wilson GS Tian A Hebbard L Duan W George J Li X. Tumoricidal Effects of the JAK Inhibitor Ruxolitinib (INC424) on Hepatocellular Carcinoma In Vitro. Cancer Lett (2013) 341: 224–30. doi: 10.1016/j.canlet.2013.08.009 23941832 · DOI
  102. [106]Thompson KJ Lau KN Johnson S Martinie JB Iannitti DA Mckillop IH. Leptin Inhibits Hepatocellular Carcinoma Proliferation via P38-MAPK-Dependent Signalling. HPB (Oxf) (2011) 13: 225–33. doi: 10.1111/j.1477-2574.2010.00259.x PMC3081622 21418127 · DOI
  103. [107]Toh TB Lim JJ Hooi L Rashid MBMA Chow EK. Targeting Jak/Stat Pathway as a Therapeutic Strategy Against SP/CD44+ Tumorigenic Cells in Akt/β-Catenin-Driven Hepatocellular Carcinoma. J Hepatol (2020) 72: 104–18. doi: 10.1016/j.jhep.2019.08.035 31541681 · DOI
  104. [108]Jung KH Yoo W Stevenson HL Deshpande D Shen H Gagea M. Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice. Clin Cancer Res (2017) 23: 5537–46. doi: 10.1158/1078-0432.CCR-16-2253 PMC5873583 28533225 · DOI · Paper page
  105. [109]Zuo M Li C Lin J Javle M. LLL12, A Novel Small Inhibitor Targeting STAT3 for Hepatocellular Carcinoma Therapy. Oncotarget (2015) 6(13): 10940–9. doi: 10.18632/oncotarget.3458 PMC4484430 25883212 · DOI
  106. [110]Hu Z Luo D Wang D Ma L Zhao Y Li L. IL-17 Activates the IL-6/STAT3 Signal Pathway in the Proliferation of Hepatitis B Virus-Related Hepatocellular Carcinoma. Cell Physiol Biochem (2017) 43: 2379–90. doi: 10.1159/000484390 29073625 · DOI
  107. [111]Okusaka T Ueno H Ikeda M Mitsunaga S Ozaka M Ishii H. Phase 1 and Pharmacological Trial of OPB-31121, a Signal Transducer and Activator of Transcription-3 Inhibitor, in Patients With Advanced Hepatocellular Carcinoma. Hepatol Res (2015) 45: 1283–91. doi: 10.1111/hepr.12504 25676869 · DOI
  108. [113]Chiablaem K Lirdprapamongkol K Keeratichamroen S Surarit R Svasti J. Curcumin suppresses Vasculogenic Mimicry Capacity of Hepatocellular Carcinoma Cells Through STAT3 and PI3K/AKT Inhibition. Anticancer Res (2014) 34: 1857–64. 24692720
  109. [114]Zhang X Yue P Page BD Li T Zhao W Namanja AT. Orally Bioavailable Small-Molecule Inhibitor of Transcription Factor Stat3 Regresses Human Breast and Lung Cancer Xenografts. Proc Natl Acad Sci USA (2012) 109: 9623–8. doi: 10.1073/pnas.1121606109 PMC3386073 22623533 · DOI
  110. [115]Miyoshi K Takaishi M Nakajima K Ikeda M Kanda T Tarutani M. Stat3 as a Therapeutic Target for the Treatment of Psoriasis: A Clinical Feasibility Study With STA-21, a Stat3 Inhibitor. J Invest Dermatol (2011) 131: 108–17. doi: 10.1038/jid.2010.255 20811392 · DOI
  111. [116]Zhang W Liu Y Yan Z Yang H Sun W Yao Y. IL-6 Promotes PD-L1 Expression in Monocytes and Macrophages by Decreasing Protein Tyrosine Phosphatase Receptor Type O Expression in Human Hepatocellular Carcinoma. J Immunother Cancer (2020) 8: e000285. doi: 10.1136/jitc-2019-000285 32581055 PMC7319788 · DOI
  112. [117]Lu X Wo G Li B Xu C Wu J Jiang C. The Anti-Inflammatory NHE-06 Restores Antitumor Immunity by Targeting NF-Kappab/IL-6/STAT3 signaling in Hepatocellular Carcinoma. BioMed Pharmacother (2018) 102: 420–7. doi: 10.1016/j.biopha.2018.03.099 29574282 · DOI
  113. [118]Zhou YF Song SS Tian MX Tang Z Wang H Fang Y. Cystathionine Beta-Synthase Mediated PRRX2/IL-6/STAT3 inactivation Suppresses Tregs Infiltration and Induces Apoptosis to Inhibit HCC Carcinogenesis. J Immunother Cancer (2021) 9: e003031. doi: 10.1136/jitc-2021-003031 34413167 PMC8380548 · DOI
  114. [119]Cao W Zhang Y Li A Yu P Song L Liang J. Curcumin Reverses Hepatic Epithelial Mesenchymal Transition Induced by Trichloroethylene by Inhibiting IL-6r/Stat3. Toxicol Mech Methods (2021) 31: 589–99. doi: 10.1080/15376516.2021.1941463 34233590 · DOI

Authors
Xu, J., Lin, H., Wu, G., Zhu, M., & Li, M.
Affiliations
Hainan Medical University (CN)
Corresponding author
  • Zhu, Mingyue
  • Li, Mengsen
ORCID
Venue
Frontiers in Oncology
Publisher
Frontiers Media SA
Published
2021-12-15
Volume
11
Pages
760971-760971
ISSN
2234-943X (ISSN-L)
DOI
10.3389/fonc.2021.760971
PMC
PMC8714735
OpenAlex
W4200108102
Cited by
228
References
122
Citations by year
2026: 47 · 2025: 51 · 2024: 51 · 2023: 51 · 2022: 28
FWCI
3.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (82060514, 81660463, [2019]22, 20168263, 81960519)
  • Natural Science Foundation of Hainan Province (2019CR204, 2019CXTD406, 20168263, JBGS202106, 820QN403)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
hepatocellular carcinoma, interleukin-6, STAT3 signaling, IL-6/STAT3 pathway, therapeutic target, IL-6 receptor, JAK signaling, immunosuppressive tumor microenvironment, STAT3 inhibitor, curcumin, drug resistance, tumor progression

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