Skip to main content Skip to main navigation menu Skip to site footer

Crosstalk between hypoxia and inflammation in non-Hodgkin lymphoma

  • Eko Adhi Pangarsa ,
  • Daniel Rizky ,
  • Budi Setiawan ,
  • Damai Santosa ,
  • Sofia Mubarika Haryana ,
  • Catharina Suharti ,


Tumor hypoxia is a well-known biological circumstance that has an impact on cancer growth and metastasis. This phenomenon is associated with poor patient outcomes, particularly in patients with non-Hodgkin lymphoma. As the tumor mass grows, aggressive lymphoid malignancies necessitate a constant increase in perfusion, activating the hypoxia-inducible factor (HIF)-1α. HIF-1α is an important regulator widely discussed in various studies and pathological states that influence the expression of several genes through transcriptional regulation, including metabolism/respiration, cell cycle, apoptosis, proliferation, angiogenesis, and others that may favor tumor growth. Tumor hypoxia also induces the expression of other important regulators, such as microRNA-210 (miR-210) and Nuclear Factor Kappa B (NF-κB), which propagate the tumorigenesis process. This article reviewed the molecular mechanisms of how HIF-1α correlates with NF-κB and other factors in non-Hodgkin lymphoma patients.


  1. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood [Internet]. 2016;127(20):2375–90. Available from:
  2. Cabanillas F. Non-Hodgkin's Lymphoma: The Old and the New. Clin Lymphoma Myeloma Leuk [Internet]. 2011;11:S87–90. Available from:
  3. Bowzky A, Ajithkumar T, Behan S HD. Non Hodgkin lymphoma. BMJ. 2018;362(August):1–7.
  4. Riedell PA, Smith SM. Double hit and double expressors in lymphoma: Definition and treatment. Cancer [Internet]. 2018;124(24):4622–32. Available from:
  5. Petrova V, Annicchiarico-Petruzzelli M, Melino G, Amelio I. The hypoxic tumour microenvironment. Oncogenesis [Internet]. 2018;7(1):10. Available from:
  6. Matolay O, Méhes G. Sustain, Adapt, and Overcome—Hypoxia Associated Changes in the Progression of Lymphatic Neoplasia. Front Oncol [Internet]. 2019;9. Available from:
  7. Sahu A, Kwon I, Tae G. Improving cancer therapy through the nanomaterials-assisted alleviation of hypoxia. Biomaterials [Internet]. 2020;228:119578. Available from:
  8. Dhani N, Fyles A, Hedley D, Milosevic M. The Clinical Significance of Hypoxia in Human Cancers. Semin Nucl Med [Internet]. 2015;45(2):110–21. Available from:
  9. Koh MY, Powis G. Passing the baton: the HIF switch. Trends Biochem Sci [Internet]. 2012;37(9):364–72. Available from:
  10. Eales KL, Hollinshead KER, Tennant DA. Hypoxia and metabolic adaptation of cancer cells. Oncogenesis [Internet]. 2016;5(1):e190–e190. Available from:
  11. Balamurugan K. HIF-1 at the crossroads of hypoxia, inflammation, and cancer. Int J Cancer [Internet]. 2016;138(5):1058–66. Available from:
  12. Graham K, Unger E. Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment. Int J Nanomedicine [Internet]. 2018;13:6049–58. Available from:
  13. Vaupel P. Hypoxia and Aggressive Tumor Phenotype: Implications for Therapy and Prognosis. Oncologist [Internet]. 2008;13(S3):21–6. Available from:
  14. Chen P-S, Chiu W-T, Hsu P-L, Lin S-C, Peng I-C, Wang C-Y, et al. Pathophysiological implications of hypoxia in human diseases. J Biomed Sci [Internet]. 2020;27(1):63. Available from:
  15. Bertero T, Rezzonico R, Pottier N, Mari B. Impact of MicroRNAs in the Cellular Response to Hypoxia. In 2017. p. 91–158. Available from:
  16. Shen G, Li X, Jia Y, Piazza GA, Xi Y. Hypoxia-regulated microRNAs in human cancer. Acta Pharmacol Sin [Internet]. 2013;34(3):336–41. Available from:
  17. Yeo E-J. Hypoxia and aging. Exp Mol Med [Internet]. 2019;51(6):1–15. Available from:
  18. Chan SY, Loscalzo J. MicroRNA-210: A unique and pleiotropic hypoxamir. Cell Cycle [Internet]. 2010;9(6):1072–83. Available from:
  19. Irigoyen M, García-Ruiz JC, Berra E. The hypoxia signalling pathway in haematological malignancies. Oncotarget [Internet]. 2017;8(22):36832–44. Available from:
  20. Bartels K, Grenz A, Eltzschig HK. Hypoxia and inflammation are two sides of the same coin. Proc Natl Acad Sci [Internet]. 2013;110(46):18351–2. Available from:
  21. Hong S-S, Lee H, Kim K-W. HIF-1α: a Valid Therapeutic Target for Tumor Therapy. Cancer Res Treat [Internet]. 2004;36(6):343. Available from:
  22. Lee J-W, Bae S-H, Jeong J-W, Kim S-H, Kim K-W. Hypoxia-inducible factor (HIF-1)α: its protein stability and biological functions. Exp Mol Med [Internet]. 2004;36(1):1–12. Available from:
  23. Evens AM, Sehn LH, Farinha P, Nelson BP, Raji A, Lu Y, et al. Hypoxia-Inducible Factor-1 α Expression Predicts Superior Survival in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP. J Clin Oncol [Internet]. 2010;28(6):1017–24. Available from:
  24. Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol [Internet]. 2000;88(4):1474–80. Available from:
  25. Hoogsteen IJ, Marres HAM, van der Kogel AJ, Kaanders JHAM. The Hypoxic Tumour Microenvironment, Patient Selection and Hypoxia-modifying Treatments. Clin Oncol [Internet]. 2007;19(6):385–96. Available from:
  26. Shao C, Yang F, Miao S, Liu W, Wang C, Shu Y, et al. Role of hypoxia-induced exosomes in tumor biology. Mol Cancer [Internet]. 2018;17(1):120. Available from:
  27. Wang T, Gilkes DM, Takano N, Xiang L, Luo W, Bishop CJ, et al. Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci [Internet]. 2014;111(31). Available from:
  28. King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer [Internet]. 2012;12(1):421. Available from:
  29. Tadokoro H, Umezu T, Ohyashiki K, Hirano T, Ohyashiki JH. Exosomes Derived from Hypoxic Leukemia Cells Enhance Tube Formation in Endothelial Cells. J Biol Chem [Internet]. 2013;288(48):34343–51. Available from:
  30. Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K, et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol [Internet]. 2008;141(5):672–5. Available from:
  31. Wang M, Yu F, Ding H, Wang Y, Li P, Wang K. Emerging Function and Clinical Values of Exosomal MicroRNAs in Cancer. Mol Ther Nucleic Acid. 2019;16(June):791–804.
  32. Annese T, Tamma R, De Giorgis M, Ribatti D. microRNAs Biogenesis, Functions and Role in Tumor Angiogenesis. Front Oncol [Internet]. 2020;10. Available from:
  33. Qin Q, Furong W, Baosheng L. Multiple functions of hypoxia-regulated miR-210 in cancer. J Exp Clin Cancer Res [Internet]. 2014;33(1):50. Available from:
  34. MacFarlane L-A, R. Murphy P. MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics [Internet]. 2010;11(7):537–61. Available from:
  35. Devlin C, Greco S, Martelli F, Ivan M. Critical Review miR-210 : More than a Silent Player in Hypoxia. Int Union Biochem Mol Biol. 2011;63(February):94–100.
  36. Ivan M, Huang X. miR-210: Fine-Tuning the Hypoxic Response. In 2014. p. 205–27. Available from:
  37. Fasanaro P, D'Alessandra Y, Di Stefano V, Melchionna R, Romani S, Pompilio G, et al. MicroRNA-210 Modulates Endothelial Cell Response to Hypoxia and Inhibits the Receptor Tyrosine Kinase Ligand Ephrin-A3. J Biol Chem [Internet]. 2008;283(23):15878–83. Available from:
  38. Chan SY, Zhang Y-Y, Hemann C, Mahoney CE, Zweier JL, Loscalzo J. MicroRNA-210 Controls Mitochondrial Metabolism during Hypoxia by Repressing the Iron-Sulfur Cluster Assembly Proteins ISCU1/2. Cell Metab [Internet]. 2009;10(4):273–84. Available from:
  39. Gee HE, Ivan C, Calin GA, Ivan M. HypoxamiRs and Cancer: From Biology to Targeted Therapy. Antioxid Redox Signal [Internet]. 2014;21(8):1220–38. Available from:
  40. Huang X, Zuo J. Emerging roles of miR-210 and other non-coding RNAs in the hypoxic response. Acta Biochim Biophys Sin (Shanghai) [Internet]. 2014;46(3):220–32. Available from:
  41. CHAN YC, BANERJEE J, CHOI SY, SEN CK. miR-210: The Master Hypoxamir. Microcirculation [Internet]. 2012;19(3):215–23. Available from:
  42. Oeckinghaus A, Ghosh S. The NF- B Family of Transcription Factors and Its Regulation. Cold Spring Harb Perspect Biol [Internet]. 2009;1(4):a000034–a000034. Available from:
  43. D’Ignazio L, Bandarra D, Rocha S. NF-κB and HIF crosstalk in immune responses. FEBS J [Internet]. 2016;283(3):413–24. Available from:
  44. D’Ignazio L, Rocha S. Hypoxia Induced NF-κB. Cells [Internet]. 2016;5(1):10. Available from:
  45. Hayden MS, Ghosh S. Regulation of NF-κB by TNF family cytokines. Semin Immunol [Internet]. 2014;26(3):253–66. Available from:
  46. Liu T, Zhang L, Joo D, Sun S-C. NF-κB signaling in inflammation. Signal Transduct Target Ther [Internet]. 2017;2(1):17023. Available from:
  47. Moynagh PN. The NF-κB pathway. J Cell Sci [Internet]. 2005;118(20):4589–92. Available from:
  48. Lawrence T. The Nuclear Factor NF- B Pathway in Inflammation. Cold Spring Harb Perspect Biol [Internet]. 2009;1(6):a001651–a001651. Available from:
  49. Xia Y, Shen S, Verma IM. NF-κB, an Active Player in Human Cancers. Cancer Immunol Res [Internet]. 2014;2(9):823–30. Available from:
  50. Eltzschig HK, Carmeliet P. Hypoxia and Inflammation. Schwartz RS, editor. N Engl J Med [Internet]. 2011;364(7):656–65. Available from:
  51. Bandarra D, Rocha S. A tale of two transcription factors: NF-kB and HIF crosstalk. OA Mol Cell Biol [Internet]. 2013;1(1). Available from:
  52. Carbone A, Tripodo C, Carlo-Stella C, Santoro A, Gloghini A. The Role of Inflammation in Lymphoma. In 2014. p. 315–33. Available from:
  53. de Jong D, Enblad G. Inflammatory cells and immune microenvironment in malignant lymphoma. J Intern Med [Internet]. 2008;264(6):528–36. Available from:
  54. Okada F. Inflammation-related carcinogenesis: Current findings in epidemiological trends, causes and mechanisms. Yonago Acta Med. 2014;57(2):65–72.
  55. Chan J, Aozasa K, Gaulard P. DLBCL associated with chronic inflammation. In: Swerdlow SH, Campo E, Harris N, editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008. p. 245–6.
  56. Loong F, Chan ACL, Ho BCS, Chau YP, Lee HY, Cheuk W, et al. Diffuse large B-cell lymphoma associated with chronic inflammation as an incidental finding and new clinical scenarios. Mod Pathol. 2010;23(4):493–501.
  57. Xia L, Tan S, Zhou Y, Lin J, Wang H, Oyang L, et al. Role of the NF-kappaB-signaling pathway in cancer. Onco Targets Ther [Internet]. 2018;11:2063–73. Available from:
  58. Liu T, Zhang L, Joo D, Sun S. NF- κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:e17023.
  59. Taniguchi K, Karin M. NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol [Internet]. 2018;18(5):309–24. Available from:
  60. Koong AC, Chen EY, Giaccia AJ. Hypoxia causes the activation of nuclear factor kappa B through the phosphorylation of I kappa B alpha on tyrosine residues. Cancer Res [Internet]. 1994;54(6):1425–30. Available from:
  61. Culver C, Sundqvist A, Mudie S, Melvin A, Xirodimas D, Rocha S. Mechanism of Hypoxia-Induced NF-κB. Mol Cell Biol [Internet]. 2010;30(20):4901–21. Available from:
  62. Palazon A, Goldrath AW, Nizet V, Johnson RS. HIF Transcription Factors, Inflammation, and Immunity. Immunity [Internet]. 2014;41(4):518–28. Available from:
  63. Bruning U, Fitzpatrick SF, Frank T, Birtwistle M, Taylor CT, Cheong A. NFκB and HIF display synergistic behaviour during hypoxic inflammation. Cell Mol Life Sci [Internet]. 2012;69(8):1319–29. Available from:
  64. Evens AM, Schumacker PT, Helenowski IB, Singh ATK, Dokic D, Keswani A, et al. Hypoxia inducible factor-alpha activation in lymphoma and relationship to the thioredoxin family. Br J Haematol [Internet]. 2008;141(5):676–80. Available from:
  65. Sircar A, Chowdhury S, Hart A, Bell W, Singh S, Sehgal L, et al. Impact and Intricacies of Bone Marrow Microenvironment in B-cell Lymphomas: From Biology to Therapy. Int J Mol Sci [Internet]. 2020;21(3):904. Available from:
  66. Ribatti D, Nico B, Ranieri G, Specchia G, Vacca A. The Role of Angiogenesis in Human Non-Hodgkin Lymphomas. Neoplasia [Internet]. 2013;15(3):231–8. Available from:
  67. Salven P, Orpana A, Teerenhovi L, Joensuu H. Simultaneous elevation in the serum concentrations of the angiogenic growth factors VEGF and bFGF is an independent predictor of poor prognosis in non-Hodgkin lymphoma: a single-institution study of 200 patients. Blood [Internet]. 2000;96(12):3712–8. Available from:
  68. Staudt LM. Oncogenic Activation of NF- B. Cold Spring Harb Perspect Biol [Internet]. 2010;2(6):a000109–a000109. Available from:
  69. Kennedy R, Klein U. Aberrant Activation of NF-κB Signalling in Aggressive Lymphoid Malignancies. Cells [Internet]. 2018;7(11):189. Available from:
  70. Demchenko YN, Kuehl WM. A critical role for the NFkB pathway in multiple myeloma. Oncotarget [Internet]. 2010;1(1):59–68. Available from:
  71. Compagno M, Lim WK, Grunn A, Nandula S V., Brahmachary M, Shen Q, et al. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma. Nature [Internet]. 2009;459(7247):717–21. Available from:
  72. Zhang B, Calado DP, Wang Z, Fröhler S, Köchert K, Qian Y, et al. An Oncogenic Role for Alternative NF-κB Signaling in DLBCL Revealed upon Deregulated BCL6 Expression. Cell Rep [Internet]. 2015;11(5):715–26. Available from:

How to Cite

Adhi Pangarsa, E., Rizky, D., Setiawan, B., Santosa, D., Mubarika Haryana, S., & Suharti, C. (2022). Crosstalk between hypoxia and inflammation in non-Hodgkin lymphoma. Bali Medical Journal, 11(3), 1063–1073.




Search Panel