Skip to main content
SpringerLink
Log in

EMT and Inflammation: Crossroads in HCC

  • Review Article
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

Hepatocellular carcinoma is one of the major causes of cancer-related deaths worldwide and is associated with several inflammatory mediators, since 90% of HCCs occur based on chronic hepatitis B or C, alcoholism or increasingly metabolic syndrome-associated inflammation. EMT is a physiological process, with coordinated changes in epithelial gene signatures and is regulated by multiple factors, including cytokines and growth factors such as TGFβ, EGF, and FGF. Recent reports propose a strong association between EMT and inflammation, which is also correlated with tumor aggressiveness and poor outcomes. Cellular heterogeneity results collectively as an outcome of EMT, inflammation, and the tumor microenvironment, and it plays a fundamental role in the progression, complexity of cancer, and chemoresistance. In this review, we highlight recent developments concerning the association of EMT and inflammation in the context of HCC progression. Identifying potential EMT-related biomarkers and understanding EMT regulatory molecules will likely contribute to promising developments in clinical practice and will be a valuable tool for predicting metastasis in general and specifically in HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data Availability

Not applicable.

References

  1. Brabletz T. To differentiate or not–routes towards metastasis. Nat Rev Cancer. 2012;12(6):425–36. https://doi.org/10.1038/nrc3265.

    Article  CAS  PubMed  Google Scholar 

  2. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8. https://doi.org/10.1172/JCI39104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kim DH, Xing T, Yang Z, Dudek R, Lu Q, et al. Epithelial mesenchymal transition in embryonic development, tissue repair and cancer: a comprehensive overview. J Clin Med. 2017;7(1). https://doi.org/10.3390/jcm7010001.

  4. Theveneau E, Mayor R. Neural crest delamination and migration: from epithelium-to-mesenchyme transition to collective cell migration. Dev Biol. 2012;366(1):34–54. https://doi.org/10.1016/j.ydbio.2011.12.041.

    Article  CAS  PubMed  Google Scholar 

  5. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90. https://doi.org/10.1016/j.cell.2009.11.007.

    Article  CAS  PubMed  Google Scholar 

  6. Yokoyama S, Asahara H. The myogenic transcriptional network. Cell Mol Life Sci. 2011;68(11):1843–9. https://doi.org/10.1007/s00018-011-0629-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Haensel D, Dai X. Epithelial-to-mesenchymal transition in cutaneous wound healing: where we are and where we are heading. Dev Dyn. 2018;247(3):473–80. https://doi.org/10.1002/dvdy.24561.

    Article  PubMed  Google Scholar 

  8. Stone RC, Pastar I, Ojeh N, Chen V, Liu S, et al. Epithelial-mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res. 2016;365(3):495–506. https://doi.org/10.1007/s00441-016-2464-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bakir B, Chiarella AM, Pitarresi JR, Rustgi AK. EMT, MET, Plasticity, and Tumor Metastasis. Trends Cell Biol. 2020;30(10):764–76. https://doi.org/10.1016/j.tcb.2020.07.003.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lu W, Kang Y. Epithelial-mesenchymal plasticity in cancer progression and metastasis. Dev Cell. 2019;49(3):361–74. https://doi.org/10.1016/j.devcel.2019.04.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ribatti D, Tamma R, Annese T. Epithelial-mesenchymal transition in cancer: a historical overview. Transl Oncol. 2020;13(6): 100773. https://doi.org/10.1016/j.tranon.2020.100773.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Suarez-Carmona M, Lesage J, Cataldo D, Gilles C. EMT and inflammation: inseparable actors of cancer progression. Mol Oncol. 2017;11(7):805–23. https://doi.org/10.1002/1878-0261.12095.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhou C, Liu J, Tang Y, Liang X. Inflammation linking EMT and cancer stem cells. Oral Oncol. 2012;48(11):1068–75. https://doi.org/10.1016/j.oraloncology.2012.06.005.

    Article  CAS  PubMed  Google Scholar 

  14. Chan LK, Tsui YM, Ho DW, Ng IO. Cellular heterogeneity and plasticity in liver cancer. Semin Cancer Biol. 2021. https://doi.org/10.1016/j.semcancer.2021.02.015.

    Article  PubMed  Google Scholar 

  15. van Zijl F, Zulehner G, Petz M, Schneller D, Kornauth C, et al. Epithelial-mesenchymal transition in hepatocellular carcinoma. Future Oncol. 2009;5(8):1169–79. https://doi.org/10.2217/fon.09.91.

    Article  PubMed  Google Scholar 

  16. Bishayee A. The role of inflammation and liver cancer. Adv Exp Med Biol. 2014;816:401–35. https://doi.org/10.1007/978-3-0348-0837-8_16.

    Article  CAS  PubMed  Google Scholar 

  17. Refolo MG, Messa C, Guerra V, Carr BI, D'Alessandro R. Inflammatory mechanisms of HCC development. Cancers (Basel). 2020;12(3). https://doi.org/10.3390/cancers12030641.

  18. Yu LX, Ling Y, Wang HY. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis Oncol. 2018;2(1):6. https://doi.org/10.1038/s41698-018-0048-z.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kew MC. Aflatoxins as a cause of hepatocellular carcinoma. J Gastrointestin Liver Dis. 2013;22(3):305–10.

    PubMed  Google Scholar 

  20. Severi T, van Malenstein H, Verslype C, van Pelt JF. Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets. Acta Pharmacol Sin. 2010;31(11):1409–20. https://doi.org/10.1038/aps.2010.142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Budhu A, Wang XW. The role of cytokines in hepatocellular carcinoma. J Leukoc Biol. 2006;80(6):1197–213. https://doi.org/10.1189/jlb.0506297.

    Article  CAS  PubMed  Google Scholar 

  22. Kany S, Vollrath JT, Relja B. Cytokines in inflammatory disease. Int J Mol Sci. 2019;20(23). https://doi.org/10.3390/ijms20236008.

  23. Ding K, Fan L, Chen S, Wang Y, Yu H, et al. Overexpression of osteopontin promotes resistance to cisplatin treatment in HCC. Oncol Rep. 2015;34(6):3297–303. https://doi.org/10.3892/or.2015.4306.

    Article  CAS  PubMed  Google Scholar 

  24. Dong Q, Zhu X, Dai C, Zhang X, Gao X, et al. Osteopontin promotes epithelial-mesenchymal transition of hepatocellular carcinoma through regulating vimentin. Oncotarget. 2016;7(11):12997–3012. https://doi.org/10.18632/oncotarget.7016.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Cabiati M, Gaggini M, Cesare MM, Caselli C, De Simone P, et al. Osteopontin in hepatocellular carcinoma: a possible biomarker for diagnosis and follow-up. Cytokine. 2017;99:59–65. https://doi.org/10.1016/j.cyto.2017.07.004.

    Article  CAS  PubMed  Google Scholar 

  26. Shang S, Plymoth A, Ge S, Feng Z, Rosen HR, et al. Identification of osteopontin as a novel marker for early hepatocellular carcinoma. Hepatology. 2012;55(2):483–90. https://doi.org/10.1002/hep.24703.

    Article  CAS  PubMed  Google Scholar 

  27. Kim H, Park YN. Hepatocellular carcinomas expressing ‘stemness’-related markers: clinicopathological characteristics. Dig Dis. 2014;32(6):778–85. https://doi.org/10.1159/000368021.

    Article  PubMed  Google Scholar 

  28. Kong FF, Qu ZQ, Yuan HH, Wang JY, Zhao M, et al. Overexpression of FOXM1 is associated with EMT and is a predictor of poor prognosis in non-small cell lung cancer. Oncol Rep. 2014;31(6):2660–8. https://doi.org/10.3892/or.2014.3129.

    Article  CAS  PubMed  Google Scholar 

  29. Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, et al. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003;116(Pt 3):499–511.

    Article  CAS  PubMed  Google Scholar 

  30. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96. https://doi.org/10.1038/nrm3758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Giannelli G, Koudelkova P, Dituri F, Mikulits W. Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J Hepatol. 2016;65(4):798–808. https://doi.org/10.1016/j.jhep.2016.05.007.

    Article  CAS  PubMed  Google Scholar 

  32. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7. https://doi.org/10.1038/nature01322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhou YM, Cao L, Li B, Zhang RX, Sui CJ, et al. Clinicopathological significance of ZEB1 protein in patients with hepatocellular carcinoma. Ann Surg Oncol. 2012;19(5):1700–6. https://doi.org/10.1245/s10434-011-1772-6.

    Article  PubMed  Google Scholar 

  34. Sreekumar R, Emaduddin M, Al-Saihati H, Moutasim K, Chan J, et al. Protein kinase C inhibitors override ZEB1-induced chemoresistance in HCC. Cell Death Dis. 2019;10(10):703. https://doi.org/10.1038/s41419-019-1885-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Al-Ismaeel Q, Neal CP, Al-Mahmoodi H, Almutairi Z, Al-Shamarti I, et al. ZEB1 and IL-6/11-STAT3 signalling cooperate to define invasive potential of pancreatic cancer cells via differential regulation of the expression of S100 proteins. Br J Cancer. 2019;121(1):65–75. https://doi.org/10.1038/s41416-019-0483-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. de Barrios O, Sanchez-Moral L, Cortes M, Ninfali C, Profitos-Peleja N, et al. ZEB1 promotes inflammation and progression towards inflammation-driven carcinoma through repression of the DNA repair glycosylase MPG in epithelial cells. Gut. 2019;68(12):2129–41. https://doi.org/10.1136/gutjnl-2018-317294.

    Article  CAS  PubMed  Google Scholar 

  37. Katsura A, Tamura Y, Hokari S, Harada M, Morikawa M, et al. ZEB1-regulated inflammatory phenotype in breast cancer cells. Mol Oncol. 2017;11(9):1241–62. https://doi.org/10.1002/1878-0261.12098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ricciardi M, Zanotto M, Malpeli G, Bassi G, Perbellini O, et al. Epithelial-to-mesenchymal transition (EMT) induced by inflammatory priming elicits mesenchymal stromal cell-like immune-modulatory properties in cancer cells. Br J Cancer. 2015;112(6):1067–75. https://doi.org/10.1038/bjc.2015.29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gugnoni M, Ciarrocchi A. Long noncoding RNA and epithelial mesenchymal transition in cancer. Int J Mol Sci. 2019;20(8). https://doi.org/10.3390/ijms20081924.

  40. Lopez-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009;1(6–7):303–14. https://doi.org/10.1002/emmm.200900043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Aruga N, Kijima H, Masuda R, Onozawa H, Yoshizawa T, et al. Epithelial-mesenchymal transition (EMT) is correlated with patient’s prognosis of lung squamous cell carcinoma. Tokai J Exp Clin Med. 2018;43(1):5–13.

    CAS  PubMed  Google Scholar 

  42. Deshmukh AP, Vasaikar SV, Tomczak K, Tripathi S, den Hollander P, et al. Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing. Proc Natl Acad Sci USA. 2021;118(19). https://doi.org/10.1073/pnas.2102050118.

  43. Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014;7(344):re8. https://doi.org/10.1126/scisignal.2005189.

  44. Moustakas A, Heldin CH. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 2007;98(10):1512–20. https://doi.org/10.1111/j.1349-7006.2007.00550.x.

    Article  CAS  PubMed  Google Scholar 

  45. Fuxe J, Karlsson MC. TGF-beta-induced epithelial-mesenchymal transition: a link between cancer and inflammation. Semin Cancer Biol. 2012;22(5–6):455–61. https://doi.org/10.1016/j.semcancer.2012.05.004.

    Article  CAS  PubMed  Google Scholar 

  46. Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S. TGF-beta - an excellent servant but a bad master. J Transl Med. 2012;10:183. https://doi.org/10.1186/1479-5876-10-183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yang L, Moses HL. Transforming growth factor beta: tumor suppressor or promoter? Are host immune cells the answer? Cancer Res. 2008;68(22):9107–11. https://doi.org/10.1158/0008-5472.CAN-08-2556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dituri F, Mancarella S, Cigliano A, Chieti A, Giannelli G. TGF-beta as multifaceted orchestrator in HCC progression: signaling, EMT, immune microenvironment, and novel therapeutic perspectives. Semin Liver Dis. 2019;39(1):53–69. https://doi.org/10.1055/s-0038-1676121.

    Article  CAS  PubMed  Google Scholar 

  49. Su Q, Fan M, Wang J, Ullah A, Ghauri MA, et al. Sanguinarine inhibits epithelial-mesenchymal transition via targeting HIF-1alpha/TGF-beta feed-forward loop in hepatocellular carcinoma. Cell Death Dis. 2019;10(12):939. https://doi.org/10.1038/s41419-019-2173-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang J, Zhang Q, Lou Y, Fu Q, Chen Q, et al. Hypoxia-inducible factor-1alpha/interleukin-1beta signaling enhances hepatoma epithelial-mesenchymal transition through macrophages in a hypoxic-inflammatory microenvironment. Hepatology. 2018;67(5):1872–89. https://doi.org/10.1002/hep.29681.

    Article  CAS  PubMed  Google Scholar 

  51. Tam SY, Wu VWC, Law HKW. Hypoxia-induced epithelial-mesenchymal transition in cancers: HIF-1alpha and beyond. Front Oncol. 2020;10:486. https://doi.org/10.3389/fonc.2020.00486.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Yeo CD, Kang N, Choi SY, Kim BN, Park CK, et al. The role of hypoxia on the acquisition of epithelial-mesenchymal transition and cancer stemness: a possible link to epigenetic regulation. Korean J Intern Med. 2017;32(4):589–99. https://doi.org/10.3904/kjim.2016.302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kung-Chun Chiu D, Pui-Wah Tse A, Law CT, Ming-Jing Xu I, Lee D, et al. Hypoxia regulates the mitochondrial activity of hepatocellular carcinoma cells through HIF/HEY1/PINK1 pathway. Cell Death Dis. 2019;10(12):934. https://doi.org/10.1038/s41419-019-2155-3.

  54. Liu Z, Tu K, Wang Y, Yao B, Li Q, et al. Hypoxia accelerates aggressiveness of hepatocellular carcinoma cells involving oxidative stress, epithelial-mesenchymal transition and non-canonical hedgehog signaling. Cell Physiol Biochem. 2017;44(5):1856–68. https://doi.org/10.1159/000485821.

    Article  CAS  PubMed  Google Scholar 

  55. Lv C, Wang S, Lin L, Wang C, Zeng K, et al. USP14 maintains HIF1-alpha stabilization via its deubiquitination activity in hepatocellular carcinoma. Cell Death Dis. 2021;12(9):803. https://doi.org/10.1038/s41419-021-04089-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yan G, Wang X, Sun C, Zheng X, Wei H, et al. Chronic alcohol consumption promotes diethylnitrosamine-induced hepatocarcinogenesis via immune disturbances. Sci Rep. 2017;7(1):2567. https://doi.org/10.1038/s41598-017-02887-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mitra A, Yan J, Xia X, Zhou S, Chen J, et al. IL6-mediated inflammatory loop reprograms normal to epithelial-mesenchymal transition(+) metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta-deficient beta2-spectrin(+/-) mice. Hepatology. 2017;65(4):1222–36. https://doi.org/10.1002/hep.28951.

    Article  CAS  PubMed  Google Scholar 

  58. Bergmann J, Muller M, Baumann N, Reichert M, Heneweer C, et al. IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology. 2017;65(1):89–103. https://doi.org/10.1002/hep.28874.

    Article  CAS  PubMed  Google Scholar 

  59. Chen Y, Meng L, Shang H, Dou Q, Lu Z, et al. Beta2 spectrin-mediated differentiation repressed the properties of liver cancer stem cells through beta-catenin. Cell Death Dis. 2018;9(4):424. https://doi.org/10.1038/s41419-018-0456-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Deng YR, Ma HD, Tsuneyama K, Yang W, Wang YH, et al. STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib. J Autoimmun. 2013;46:25–34. https://doi.org/10.1016/j.jaut.2013.07.008.

    Article  CAS  PubMed  Google Scholar 

  61. Li Y, Chen G, Han Z, Cheng H, Qiao L, et al. IL-6/STAT3 Signaling contributes to sorafenib resistance in hepatocellular carcinoma through targeting cancer stem cells. Onco Targets Ther. 2020;13:9721–30. https://doi.org/10.2147/OTT.S262089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wael H, Yoshida R, Kudoh S, Hasegawa K, Niimori-Kita K, et al. Notch1 signaling controls cell proliferation, apoptosis and differentiation in lung carcinoma. Lung Cancer. 2014;85(2):131–40. https://doi.org/10.1016/j.lungcan.2014.05.001.

    Article  PubMed  Google Scholar 

  63. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678–89. https://doi.org/10.1038/nrm2009.

    Article  CAS  PubMed  Google Scholar 

  64. Bray SJ. Notch signalling in context. Nat Rev Mol Cell Biol. 2016;17(11):722–35. https://doi.org/10.1038/nrm.2016.94.

    Article  CAS  PubMed  Google Scholar 

  65. Allenspach EJ, Maillard I, Aster JC, Pear WS. Notch signaling in cancer. Cancer Biol Ther. 2002;1(5):466–76. https://doi.org/10.4161/cbt.1.5.159.

    Article  PubMed  Google Scholar 

  66. Aster JC, Pear WS, Blacklow SC. The varied roles of notch in cancer. Annu Rev Pathol. 2017;12:245–75. https://doi.org/10.1146/annurev-pathol-052016-100127.

    Article  CAS  PubMed  Google Scholar 

  67. Nowell CS, Radtke F. Notch as a tumour suppressor. Nat Rev Cancer. 2017;17(3):145–59. https://doi.org/10.1038/nrc.2016.145.

    Article  CAS  PubMed  Google Scholar 

  68. Zhu C, Ho YJ, Salomao MA, Dapito DH, Bartolome A, et al. Notch activity characterizes a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features. J Hepatol. 2021;74(3):613–26. https://doi.org/10.1016/j.jhep.2020.09.032.

    Article  CAS  PubMed  Google Scholar 

  69. Shen H, McElhinny AS, Cao Y, Gao P, Liu J, et al. The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis. Genes Dev. 2006;20(6):675–88. https://doi.org/10.1101/gad.1383706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang J, Zhang SM, Wu JM, Lu ZC, Yang JR, et al. Mastermind-like transcriptional coactivator 1 overexpression predicts poor prognosis in human with hepatocellular carcinoma. Ann Clin Lab Sci. 2016;46(5):502–7.

    CAS  PubMed  Google Scholar 

  71. Zema S, Pelullo M, Nardozza F, Felli MP, Screpanti I, et al. A dynamic role of mastermind-like 1: a journey through the main (path)ways between development and cancer. Front Cell Dev Biol. 2020;8: 613557. https://doi.org/10.3389/fcell.2020.613557.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Saha SK, Choi HY, Yang GM, Biswas PK, Kim K, et al. GPR50 promotes hepatocellular carcinoma progression via the notch signaling pathway through direct interaction with ADAM17. Mol Ther Oncolytics. 2020;17:332–49. https://doi.org/10.1016/j.omto.2020.04.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Garg M. Epithelial-mesenchymal transition - activating transcription factors - multifunctional regulators in cancer. World J Stem Cells. 2013;5(4):188–95. https://doi.org/10.4252/wjsc.v5.i4.188.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Wang Z, Li Y, Kong D, Sarkar FH. The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness. Curr Drug Targets. 2010;11(6):745–51. https://doi.org/10.2174/138945010791170860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP. Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J. 2004;23(5):1155–65. https://doi.org/10.1038/sj.emboj.7600069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Timmerman LA, Grego-Bessa J, Raya A, Bertran E, Perez-Pomares JM, et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 2004;18(1):99–115. https://doi.org/10.1101/gad.276304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pires BR, Mencalha AL, Ferreira GM, de Souza WF, Morgado-Diaz JA, et al. NF-kappaB is involved in the regulation of EMT genes in breast cancer cells. PLoS ONE. 2017;12(1): e0169622. https://doi.org/10.1371/journal.pone.0169622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, et al. Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell. 2009;15(5):416–28. https://doi.org/10.1016/j.ccr.2009.03.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Abbott DW, Laszczak M, Lewis JD, Su H, Moore SC, et al. Structural characterization of macroH2A containing chromatin. Biochemistry. 2004;43(5):1352–9. https://doi.org/10.1021/bi035859i.

    Article  CAS  PubMed  Google Scholar 

  80. Chang H, Li J, Qu K, Wan Y, Liu S, et al. CRIF1 overexpression facilitates tumor growth and metastasis through inducing ROS/NFkappaB pathway in hepatocellular carcinoma. Cell Death Dis. 2020;11(5):332. https://doi.org/10.1038/s41419-020-2528-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Jing Y, Han Z, Liu Y, Sun K, Zhang S, et al. Mesenchymal stem cells in inflammation microenvironment accelerates hepatocellular carcinoma metastasis by inducing epithelial-mesenchymal transition. PLoS ONE. 2012;7(8): e43272. https://doi.org/10.1371/journal.pone.0043272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta. 2014;1843(11):2563–82. https://doi.org/10.1016/j.bbamcr.2014.05.014.

    Article  CAS  PubMed  Google Scholar 

  83. Hughes CE, Nibbs RJB. A guide to chemokines and their receptors. FEBS J. 2018;285(16):2944–71. https://doi.org/10.1111/febs.14466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Huang F, Geng XP. Chemokines and hepatocellular carcinoma. World J Gastroenterol. 2010;16(15):1832–6. https://doi.org/10.3748/wjg.v16.i15.1832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sarvaiya PJ, Guo D, Ulasov I, Gabikian P, Lesniak MS. Chemokines in tumor progression and metastasis. Oncotarget. 2013;4(12):2171–85. https://doi.org/10.18632/oncotarget.1426.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017;17(9):559–72. https://doi.org/10.1038/nri.2017.49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Liang CM, Chen L, Hu H, Ma HY, Gao LL, et al. Chemokines and their receptors play important roles in the development of hepatocellular carcinoma. World J Hepatol. 2015;7(10):1390–402. https://doi.org/10.4254/wjh.v7.i10.1390.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Liu Q, Li A, Tian Y, Wu JD, Liu Y, et al. The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev. 2016;31:61–71. https://doi.org/10.1016/j.cytogfr.2016.08.002.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Batlle R, Andres E, Gonzalez L, Llonch E, Igea A, et al. Regulation of tumor angiogenesis and mesenchymal-endothelial transition by p38alpha through TGF-beta and JNK signaling. Nat Commun. 2019;10(1):3071. https://doi.org/10.1038/s41467-019-10946-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gunderson AJ, Yamazaki T, McCarty K, Fox N, Phillips M, et al. TGFbeta suppresses CD8(+) T cell expression of CXCR3 and tumor trafficking. Nat Commun. 2020;11(1):1749. https://doi.org/10.1038/s41467-020-15404-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Yang L. TGFbeta and cancer metastasis: an inflammation link. Cancer Metastasis Rev. 2010;29(2):263–71. https://doi.org/10.1007/s10555-010-9226-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Barashi N, Weiss ID, Wald O, Wald H, Beider K, et al. Inflammation-induced hepatocellular carcinoma is dependent on CCR5 in mice. Hepatology. 2013;58(3):1021–30. https://doi.org/10.1002/hep.26403.

    Article  CAS  PubMed  Google Scholar 

  93. Singh SK, Mishra MK, Rivers BM, Gordetsky JB, Bae S, et al. Biological and clinical significance of the CCR5/CCL5 axis in hepatocellular carcinoma. Cancers (Basel). 2020;12(4). https://doi.org/10.3390/cancers12040883.

  94. Kopitar-Jerala N. The role of interferons in inflammation and inflammasome activation. Front Immunol. 2017;8:873. https://doi.org/10.3389/fimmu.2017.00873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Walter MR. The role of structure in the biology of interferon signaling. Front Immunol. 2020;11: 606489. https://doi.org/10.3389/fimmu.2020.606489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rauch I, Muller M, Decker T. The regulation of inflammation by interferons and their STATs. JAKSTAT. 2013;2(1): e23820. https://doi.org/10.4161/jkst.23820.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol. 2005;5(5):375–86. https://doi.org/10.1038/nri1604.

    Article  CAS  PubMed  Google Scholar 

  98. Wang H, Brown J, Garcia CA, Tang Y, Benakanakere MR, et al. The role of glycogen synthase kinase 3 in regulating IFN-beta-mediated IL-10 production. J Immunol. 2011;186(2):675–84. https://doi.org/10.4049/jimmunol.1001473.

    Article  CAS  PubMed  Google Scholar 

  99. Romerio F, Riva A, Zella D. Interferon-alpha2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism. Br J Cancer. 2000;83(4):532–8. https://doi.org/10.1054/bjoc.2000.1263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yeh YH, Hsiao HF, Yeh YC, Chen TW, Li TK. Inflammatory interferon activates HIF-1alpha-mediated epithelial-to-mesenchymal transition via PI3K/AKT/mTOR pathway. J Exp Clin Cancer Res. 2018;37(1):70. https://doi.org/10.1186/s13046-018-0730-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Herzer K, Hofmann TG, Teufel A, Schimanski CC, Moehler M, et al. IFN-alpha-induced apoptosis in hepatocellular carcinoma involves promyelocytic leukemia protein and TRAIL independently of p53. Cancer Res. 2009;69(3):855–62. https://doi.org/10.1158/0008-5472.CAN-08-2831.

    Article  CAS  PubMed  Google Scholar 

  102. Zhang Z, Zhu Y, Xu D, Li TE, Li JH, et al. IFN-alpha facilitates the effect of sorafenib via shifting the M2-like polarization of TAM in hepatocellular carcinoma. Am J Transl Res. 2021;13(1):301–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang H, Liu J, Hu X, Liu S, He B. Prognostic and therapeutic values of tumor necrosis factor-alpha in hepatocellular carcinoma. Med Sci Monit. 2016;22:3694–704. https://doi.org/10.12659/msm.899773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest. 1998;101(2):311–20. https://doi.org/10.1172/JCI1368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Popko K, Gorska E, Stelmaszczyk-Emmel A, Plywaczewski R, Stoklosa A, et al. Proinflammatory cytokines Il-6 and TNF-alpha and the development of inflammation in obese subjects. Eur J Med Res. 2010;15(Suppl 2):120–2. https://doi.org/10.1186/2047-783x-15-s2-120.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene. 2009;28(33):2940–7. https://doi.org/10.1038/onc.2009.180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wendt MK, Balanis N, Carlin CR, Schiemann WP. STAT3 and epithelial-mesenchymal transitions in carcinomas. JAKSTAT. 2014;3(1): e28975. https://doi.org/10.4161/jkst.28975.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Gyamfi J, Lee YH, Eom M, Choi J. Interleukin-6/STAT3 signalling regulates adipocyte induced epithelial-mesenchymal transition in breast cancer cells. Sci Rep. 2018;8(1):8859. https://doi.org/10.1038/s41598-018-27184-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lin RJ, Afshar-Kharghan V, Schafer AI. Paraneoplastic thrombocytosis: the secrets of tumor self-promotion. Blood. 2014;124(2):184–7. https://doi.org/10.1182/blood-2014-03-562538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Porta C, De Amici M, Quaglini S, Paglino C, Tagliani F, et al. Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma. Ann Oncol. 2008;19(2):353–8. https://doi.org/10.1093/annonc/mdm448.

    Article  CAS  PubMed  Google Scholar 

  111. Bevilacqua MP, Pober JS, Wheeler ME, Cotran RS, Gimbrone MA, Jr. Interleukin-1 activation of vascular endothelium. Effects on procoagulant activity and leukocyte adhesion. Am J Pathol. 1985;121(3):394–403.

  112. Faletti L, Peintner L, Neumann S, Sandler S, Grabinger T, et al. TNFalpha sensitizes hepatocytes to FasL-induced apoptosis by NFkappaB-mediated Fas upregulation. Cell Death Dis. 2018;9(9):909. https://doi.org/10.1038/s41419-018-0935-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Wang Y, Xu J, Zhang X, Wang C, Huang Y, et al. TNF-alpha-induced LRG1 promotes angiogenesis and mesenchymal stem cell migration in the subchondral bone during osteoarthritis. Cell Death Dis. 2017;8(3): e2715. https://doi.org/10.1038/cddis.2017.129.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Wang H, Wang HS, Zhou BH, Li CL, Zhang F, et al. Epithelial-mesenchymal transition (EMT) induced by TNF-alpha requires AKT/GSK-3beta-mediated stabilization of snail in colorectal cancer. PLoS ONE. 2013;8(2): e56664. https://doi.org/10.1371/journal.pone.0056664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Jang MK, Kim HS, Chung YH. Clinical aspects of tumor necrosis factor-alpha signaling in hepatocellular carcinoma. Curr Pharm Des. 2014;20(17):2799–808. https://doi.org/10.2174/13816128113199990587.

    Article  CAS  PubMed  Google Scholar 

  116. Page MJ, Bester J, Pretorius E. The inflammatory effects of TNF-alpha and complement component 3 on coagulation. Sci Rep. 2018;8(1):1812. https://doi.org/10.1038/s41598-018-20220-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Neophytou, C.M., M. Panagi, T. Stylianopoulos, and P. Papageorgis, The role of tumor microenvironment in cancer metastasis: molecular mechanisms and therapeutic opportunities. Cancers (Basel), 2021. 13(9). https://doi.org/10.3390/cancers13092053.

  118. Kim J, Bae JS. Tumor-Associated macrophages and neutrophils in tumor microenvironment. Mediators Inflamm. 2016;2016:6058147. https://doi.org/10.1155/2016/6058147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shirabe K, Mano Y, Muto J, Matono R, Motomura T, et al. Role of tumor-associated macrophages in the progression of hepatocellular carcinoma. Surg Today. 2012;42(1):1–7. https://doi.org/10.1007/s00595-011-0058-8.

    Article  CAS  PubMed  Google Scholar 

  120. Li Z, Wu T, Zheng B, Chen L. Individualized precision treatment: targeting TAM in HCC. Cancer Lett. 2019;458:86–91. https://doi.org/10.1016/j.canlet.2019.05.019.

    Article  CAS  PubMed  Google Scholar 

  121. Capece D, Fischietti M, Verzella D, Gaggiano A, Cicciarelli G, et al. The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed Res Int. 2013;2013: 187204. https://doi.org/10.1155/2013/187204.

    Article  CAS  PubMed  Google Scholar 

  122. Faurobert E, Bouin AP, Albiges-Rizo C. Microenvironment, tumor cell plasticity, and cancer. Curr Opin Oncol. 2015;27(1):64–70. https://doi.org/10.1097/CCO.0000000000000154.

    Article  CAS  PubMed  Google Scholar 

  123. Runa F, Hamalian S, Meade K, Shisgal P, Gray PC, et al. Tumor microenvironment heterogeneity: challenges and opportunities. Curr Mol Biol Rep. 2017;3(4):218–29. https://doi.org/10.1007/s40610-017-0073-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Cao MX, Jiang YP, Tang YL, Liang XH. The crosstalk between lncRNA and microRNA in cancer metastasis: orchestrating the epithelial-mesenchymal plasticity. Oncotarget. 2017;8(7):12472–83. https://doi.org/10.18632/oncotarget.13957.

    Article  PubMed  Google Scholar 

  125. Jin K, Li T, Sanchez-Duffhues G, Zhou F, Zhang L. Involvement of inflammation and its related microRNAs in hepatocellular carcinoma. Oncotarget. 2017;8(13):22145–65. https://doi.org/10.18632/oncotarget.13530.

    Article  PubMed  Google Scholar 

  126. Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS. Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene. 2009;28(40):3526–36. https://doi.org/10.1038/onc.2009.211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ha SY, Yu JI, Choi C, Kang SY, Joh JW, et al. Prognostic significance of miR-122 expression after curative resection in patients with hepatocellular carcinoma. Sci Rep. 2019;9(1):14738. https://doi.org/10.1038/s41598-019-50594-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Yu X, Zheng H, Chan MT, Wu WK. HULC: an oncogenic long non-coding RNA in human cancer. J Cell Mol Med. 2017;21(2):410–7. https://doi.org/10.1111/jcmm.12956.

    Article  CAS  PubMed  Google Scholar 

  129. Li SP, Xu HX, Yu Y, He JD, Wang Z, et al. LncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of hepatocellular carcinoma via the miR-200a-3p/ZEB1 signaling pathway. Oncotarget. 2016;7(27):42431–46. https://doi.org/10.18632/oncotarget.9883.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Sphyris N, Mani SA. pIgR: frenemy of inflammation, EMT, and HCC progression. J Natl Cancer Inst. 2011;103(22):1644–5. https://doi.org/10.1093/jnci/djr421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ai J, Tang Q, Wu Y, Xu Y, Feng T, et al. The role of polymeric immunoglobulin receptor in inflammation-induced tumor metastasis of human hepatocellular carcinoma. J Natl Cancer Inst. 2011;103(22):1696–712. https://doi.org/10.1093/jnci/djr360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Critelli R, Milosa F, Faillaci F, Condello R, Turola E, et al. Microenvironment inflammatory infiltrate drives growth speed and outcome of hepatocellular carcinoma: a prospective clinical study. Cell Death Dis. 2017;8(8): e3017. https://doi.org/10.1038/cddis.2017.395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Zhang Y, Zhang J, Chen X, Yang Z. Polymeric immunoglobulin receptor (PIGR) exerts oncogenic functions via activating ribosome pathway in hepatocellular carcinoma. Int J Med Sci. 2021;18(2):364–71. https://doi.org/10.7150/ijms.49790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ben Mousa A. Sorafenib in the treatment of advanced hepatocellular carcinoma. Saudi J Gastroenterol. 2008;14(1):40–2. https://doi.org/10.4103/1319-3767.37808.

    Article  PubMed  Google Scholar 

  135. Lv X, Fang C, Yin R, Qiao B, Shang R, et al. Agrin para-secreted by PDGF-activated human hepatic stellate cells promotes hepatocarcinogenesis in vitro and in vivo. Oncotarget. 2017;8(62):105340–55. https://doi.org/10.18632/oncotarget.22186.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Zhang QJ, Wan L, Xu HF. High expression of agrin is associated with tumor progression and poor prognosis in hepatocellular carcinoma. Math Biosci Eng. 2019;16(6):7375–83. https://doi.org/10.3934/mbe.2019368.

    Article  PubMed  Google Scholar 

  137. Lozano-Ruiz B, Gonzalez-Navajas JM. The emerging relevance of AIM2 in liver disease. Int J Mol Sci. 2020;21(18). https://doi.org/10.3390/ijms21186535.

  138. Chen SL, Liu LL, Lu SX, Luo RZ, Wang CH, et al. HBx-mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis. Mol Oncol. 2017;11(9):1225–40. https://doi.org/10.1002/1878-0261.12090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported in part by NIH grant number CA 82723 (to BIC) and TÜBİTAK grant numbers 114Z245, 117Z223, 120N556, and 219Z034 (to H.A).

Author information

Authors and Affiliations

  1. Izmir Biomedicine and Genome Center, Dokuz Eylül University Health Campus, 35340, Balçova, Izmir, Turkey

    Burcu Sengez & Hani Alotaibi

  2. Liver Transplant Institution, Inonu University, Malatya, 44280, Turkey

    Brian I. Carr

  3. Izmir International Biomedicine and Genome Institute, Dokuz Eylül University Health Campus, 35340, Balçova, Izmir, Turkey

    Hani Alotaibi

Authors
  1. Burcu Sengez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brian I. Carr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hani Alotaibi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, H. A. and B. I. C.; writing—original draft preparation, B. S.; writing—review and editing, B. I. C and H. A.; funding acquisition, B. I. C. and H. A. All the authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Hani Alotaibi.

Ethics declarations

Ethics Approval

Not applicable.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sengez, B., Carr, B.I. & Alotaibi, H. EMT and Inflammation: Crossroads in HCC. J Gastrointest Canc 54, 204–212 (2023). https://doi.org/10.1007/s12029-021-00801-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-021-00801-z

Keywords

Search

Navigation