Importance of Heme Oxygenase-1 in Gastrointestinal Cancers: Functions, Inductions, Regulations, and Signaling



Colorectal cancer (CRC) is one of the important gastrointestinal tract tumors. Heme is mainly absorbed in the colon and induces nitrosamine formation, genotoxicity,  and oxidative stress, and increases the risk of CRC.

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Heme can irritate intestinal epithelial cells and increases the proliferation of colonic mucosa. Heme can be considered as a carcinogenic agent for CRC induction. In typical situations, Heme Oxygenase-1 (HO-1) is expressed at low concentration in the gastrointestinal tract, but its expression is elevated during lesion and inflammation. Based on the multiple reports, the impact of HO-1 on tumor growth is related to the cancer cell type. Increased HO‐1 levels were also indicated in different human and animal malignancies, possibly through its contribution to tumor cell growth, metastasis, expression of angiogenic factors, and resistance to chemotherapy. Recent studies noted that HO-1 can act as an immunomodulator that suppresses immune cell maturation, activation, and infiltration. It also inhibits apoptosis through CO production that leads to p53 suppression. The upregulation of HO-1 significantly increases the endurance of colon cancer cell lines. Therefore, it is supposed that HO-1 inhibitors could become a novel antitumor agent. Lactobacillus rhamnosus and its metabolites can activate Nrf2 and improves anti-oxidant levels along with upregulation of its objective genes like HO-1, and downregulation of NF-κB which reduce phosphorylated TNF-α, IL-1β, and PAI-1.


The precise mechanism accountable for the anti-inflammatory features of HO-1 is not completely understood; nevertheless, the CO signaling function associated with the antioxidant property shown by bilirubin possibly will play an act in the improvement of inflammation.

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  1. 1.

    Arnold M, et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66(4):683–91.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Ghorbani F, et al. Application of different nanoparticles in the diagnosis of colorectal cancer. Gene Reports. 2020. p. 100896.

  3. 3.

    Thanikachalam K, Khan G. Colorectal cancer and nutrition. Nutr. 2019;11(1):164.

    CAS  Google Scholar 

  4. 4.

    Hisamuddin IM, Yang VW. Genetics of colorectal cancer. Medscape Gen Med. 2004;6(3).

  5. 5.

    Sameer ASS. Colorectal cancer: molecular mutations and polymorphisms. Front Oncol. 2013;3:114.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Wong SH, Yu J. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat Rev Gastroenterol Hepatol. 2019;16(11):690–704.

    CAS  PubMed  Google Scholar 

  7. 7.

    Baena R, Salinas P. Diet and colorectal cancer. Maturitas. 2015;80(3):258–64.

    CAS  PubMed  Google Scholar 

  8. 8.

    Martinez-Useros J, Garcia-Foncillas J. Obesity and colorectal cancer: molecular features of adipose tissue. J Transl Med. 2016;14(1):21.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Gagnière J, et al. Gut microbiota imbalance and colorectal cancer. World J Gastroenterol. 2016;22(2):501.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Jahani-Sherafat S, et al. Role of gut microbiota in the pathogenesis of colorectal cancer; a review article. Gastroenterol Hepatol Bed Bench. 2018;11(2):101.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Keikha M, et al. Potential antigen candidates for subunit vaccine development against Helicobacter pylori infection. J Cell Physiol. 2019;234(12):21460–70.

    CAS  PubMed  Google Scholar 

  12. 12.

    Kruger C, Zhou Y. Red meat and colon cancer: a review of mechanistic evidence for heme in the context of risk assessment methodology. Food Chem Toxicol. 2018;118:131–53.

    CAS  PubMed  Google Scholar 

  13. 13.

    Wu MS, et al. Pro-apoptotic effect of haem oxygenase-1 in human colorectal carcinoma cells via endoplasmic reticular stress. J Cell Mol Med. 2019;23(8):5692–704.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Onyiah JC, et al. Carbon monoxide and heme oxygenase-1 prevent intestinal inflammation in mice by promoting bacterial clearance. Gastroenterol. 2013;144(4):789–98.

    CAS  Google Scholar 

  15. 15.

    Intagliata S, et al. Heme Oxygenase-2 (HO-2) as a therapeutic target: Activators and inhibitors. Eur J Med Chem. 2019;183:111703.

  16. 16.

    Abraham NG, Kappas A. Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev. 2008;60(1):79–127.

    CAS  PubMed  Google Scholar 

  17. 17.

    Ryter SW, Alam J, Choi AM. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev. 2006;86(2):583–650.

    CAS  PubMed  Google Scholar 

  18. 18.

    Takagi T, et al. The role of heme oxygenase and carbon monoxide in inflammatory bowel disease. Redox Rep. 2010;15(5):193–201.

    CAS  PubMed  Google Scholar 

  19. 19.

    Wegiel B, et al. Heme oxygenase-1: a metabolic nike. Antioxid Redox Signal. 2014;20(11):1709–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Fang J, Akaike T, Maeda H. Antiapoptotic role of heme oxygenase (HO) and the potential of HO as a target in anticancer treatment. Apoptosis. 2004;9(1):27–35.

    CAS  PubMed  Google Scholar 

  21. 21.

    Busserolles J, et al. Heme oxygenase-1 inhibits apoptosis in Caco-2 cells via activation of Akt pathway. International J Biochem Cell Biol. 2006;38(9):1510–7.

    CAS  Google Scholar 

  22. 22.

    Maines MD, Panahian N. The heme oxygenase system and cellular defense mechanisms. In Hypoxia. Springer, 2001. p. 249–272.

  23. 23.

    Wang J, Dore S. Heme oxygenase 2 deficiency increases brain swelling and inflammation after intracerebral hemorrhage. Neurosci. 2008;155(4):1133–41.

    CAS  Google Scholar 

  24. 24.

    Keyse SM, Tyrrell RM. Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci. 1989;86(1):99–103.

    CAS  PubMed  Google Scholar 

  25. 25.

    Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284(20):13291–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Liu Y-T, et al. Heme oxygenase-1 as a potential therapeutic target in rheumatic diseases. Life Sci. 2019;218:205–12.

    CAS  PubMed  Google Scholar 

  28. 28.

    Igarashi K, Sun J. The heme-Bach1 pathway in the regulation of oxidative stress response and erythroid differentiation. Antioxid Redox Signal. 2006;8(1–2):107–18.

    CAS  PubMed  Google Scholar 

  29. 29.

    Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89–116.

    CAS  PubMed  Google Scholar 

  30. 30.

    Yousefi B, et al. Epigenetic changes in gastric cancer induction by Helicobacter pylori. J Cell Physiol. 2019;234(12):21770–84.

    CAS  PubMed  Google Scholar 

  31. 31.

    Kansanen E, et al. The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox biology. 2013;1(1):45–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Jung KA, Kwak MK Enhanced 4-hydroxynonenal resistance in KEAP1 silenced human colon cancer cells. Oxidative medicine and cellular longevity. 2013.

  33. 33.

    Hu T, et al. Clinicopathologic significance of CXCR4 and Nrf2 in colorectal cancer. J Biomed Res. 2013;27(4):283.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Wentworth CC, et al. Enteric commensal bacteria induce ERK pathway signaling via formyl peptide receptor (FPR)-dependent redox modulation of Dual specific phosphatase 3 (DUSP3). J Biol Chem. 2011:jbc-M111.268938.

  35. 35.

    Farrokhi AS, et al. Histone Deacetylase Modifications by Probiotics in Colorectal Cancer. J Gastrointest Cancer. 2019:1–11.

  36. 36.

    Hochmuth CE, et al. Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. Cell Stem Cell. 2011;8(2):188–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Xu H, et al. Protective effect of lactobacillus rhamnosus GG and its supernatant against myocardial dysfunction in obese mice exposed to intermittent hypoxia is associated with the activation of Nrf2 pathway. Int J Biol Sci. 2019;15(11):2471.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Eslami M, et al. Importance of the Microbiota Inhibitory Mechanism on the Warburg Effect in Colorectal Cancer Cells. J Gastrointest Cancer. 2019:1–10.

  39. 39.

    Goel A, Boland CR. Epigenetics of colorectal cancer. Gastroenterol. 2012;143(6):1442–1460.

  40. 40.

    Lundvig DM, Immenschuh S, Wagener FA. Heme oxygenase, inflammation, and fibrosis: the good, the bad, and the ugly? Front Pharmacol. 2012;3:81.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Takagi T. Heme Oxygenase regulates the balance of inflammatory cytokines in dextran sulfate sodium-induced colitis. Gastroenterol. 2004;126:A-564.

  42. 42.

    Schipper H, Cisse S, Stopa E. Expression of heme oxygenase-1 in the senescent and Alzheimer-diseased brain. Ann Neurol. 1995;37(6):758–68.

    CAS  PubMed  Google Scholar 

  43. 43.

    Yu X, et al. Differences in vulnerability of neurons and astrocytes to heme oxygenase-1 modulation: implications for mitochondrial ferritin. Sci Rep. 2016;6:24200.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Abraham NG, et al. Heme oxygenase: the key to renal function regulation. Am J Physiology-Renal Physiol. 2009;297(5):F1137–52.

    CAS  Google Scholar 

  45. 45.

    Farombi EO, Surh YJ. Heme oxygenase-1 as a potential therapeutic target for hepatoprotection. J Biochem Mol Biol. 2006;39(5):479–91.

    CAS  PubMed  Google Scholar 

  46. 46.

    Lau A, et al. Dual roles of Nrf2 in cancer. Pharmacol Res. 2008;58(5–6):262–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Arlt A, et al. Increased proteasome subunit protein expression and proteasome activity in colon cancer relate to an enhanced activation of nuclear factor E2-related factor 2 (Nrf2). Oncog. 2009;28(45):3983–96.

    CAS  Google Scholar 

  48. 48.

    Chang L-C, et al. Immunohistochemical study of the Nrf2 pathway in colorectal cancer: Nrf2 expression is closely correlated to Keap1 in the tumor and Bach1 in the normal tissue. Appl Immunohistochem Mol Morphol. 2013;21(6):511–7.

    CAS  PubMed  Google Scholar 

  49. 49.

    Stachel I, et al. Modulation of nuclear factor E2-related factor-2 (Nrf2) activation by the stress response gene immediate early response-3 (IER3) in colonic epithelial cells: a novel mechanism of cellular adaption to inflammatory stress. J Biol Chem. 2014;289(4):1917–29.

    CAS  PubMed  Google Scholar 

  50. 50.

    Shibata T, et al. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterol. 2008;135(4):1358–1368.

  51. 51.

    Wu S, Lu H, Bai Y. Nrf2 in cancers: a double-edged sword. Cancer Med. 2019;8(5):2252–67.

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Gonzalez-Donquiles C, et al. The NRF2 transcription factor plays a dual role in colorectal cancer: a systematic review. PLoS ONE. 2017;12(5):e0177549.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Takagi T, et al. Increased intestinal expression of heme oxygenase-1 and its localization in patients with ulcerative colitis. J Gastroenterol Hepatol. 2008;23:S229–33.

    CAS  PubMed  Google Scholar 

  54. 54.

    Oláh G, et al. Role of endogenous and exogenous nitric oxide, carbon monoxide and hydrogen sulfide in HCT116 colon cancer cell proliferation. Biochem Pharmacol. 2018;149:186–204.

    PubMed  Google Scholar 

  55. 55.

    Maestrelli P, et al. Increased expression of heme oxygenase (HO)-1 in alveolar spaces and HO-2 in alveolar walls of smokers. Am J Respir Crit Care Med. 2001;164(8):1508–13.

    CAS  PubMed  Google Scholar 

  56. 56.

    Barton S, et al. Expression of heat shock protein 32 (hemoxygenase-1) in the normal and inflamed human stomach and colon: an immunohistochemical study. Cell Stress Chaperones. 2003;8(4):329.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Paul G, et al. Analysis of intestinal haem-oxygenase-1 (HO-1) in clinical and experimental colitis. Clin Exp Immunol. 2005;140(3):547–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Marelli G, et al. Heme-oxygenase-1 production by intestinal CX3CR1+ macrophages helps to resolve inflammation and prevents carcinogenesis. Can Res. 2017;77(16):4472–85.

    CAS  Google Scholar 

  59. 59.

    Seo GS, et al. Heme oxygenase-1 promotes tumor progression and metastasis of colorectal carcinoma cells by inhibiting antitumor immunity. Oncotarget. 2015;6(23):19792–806.

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Bussolati B, et al. Bifunctional role for VEGF-induced heme oxygenase-1 in vivo: induction of angiogenesis and inhibition of leukocytic infiltration. Blood. 2004;103(3):761–6.

    CAS  PubMed  Google Scholar 

  61. 61.

    Jozkowicz A, Was H, Dulak J. Heme oxygenase-1 in tumors: is it a false friend? Antioxid Redox Signal. 2007;9(12):2099–117.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Becker JC, et al. Colonic expression of heme oxygenase-1 is associated with a better long-term survival in patients with colorectal cancer. Scand J Gastroenterol. 2007;42(7):852–8.

    CAS  PubMed  Google Scholar 

  63. 63.

    Otterbein LE, et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med. 2000;6(4):422–8.

    CAS  PubMed  Google Scholar 

  64. 64.

    Ishikawa T, et al. Different effects of constitutive nitric oxide synthase and heme oxygenase on pulmonary or liver metastasis of colon cancer in mice. Clin Exp Metas. 2003;20(5):445–50.

    CAS  Google Scholar 

  65. 65.

    Wegiel B, et al. Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth. Can Res. 2013;73(23):7009–21.

    CAS  Google Scholar 

  66. 66.

    Burada F, et al. Autophagy in colorectal cancer: an important switch from physiology to pathology. World J Gastrointest Oncol. 2015;7(11):271–84.

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    Banerjee P, et al. Heme oxygenase-1 promotes survival of renal cancer cells through modulation of apoptosis- and autophagy-regulating molecules. J Biol Chem. 2012;287(38):32113–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Tan Q, et al. Src/STAT3-dependent heme oxygenase-1 induction mediates chemoresistance of breast cancer cells to doxorubicin by promoting autophagy. Cancer Sci. 2015;106(8):1023–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Ren Q-G, et al. Low heme oxygenase-1 expression promotes gastric cancer cell apoptosis, inhibits proliferation and invasion, and correlates with increased overall survival in gastric cancer patients. Oncol Rep. 2017;38(5):2852–8.

    CAS  PubMed  Google Scholar 

  70. 70.

    Cernigliaro C, et al. Ethanol-mediated stress promotes autophagic survival and aggressiveness of colon cancer cells via activation of Nrf2/HO-1 pathway. Cancers. 2019;11(4):505.

    CAS  PubMed Central  Google Scholar 

  71. 71.

    Sakaki K, Kaufman RJ. Regulation of ER stress-induced macroautophagy by protein kinase C. Autophagy. 2008;4(6):841–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Cullinan SB, et al. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol. 2003;23(20):7198–209.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Hampton RY. ER-associated degradation in protein quality control and cellular regulation. Curr Opin Cell Biol. 2002;14(4):476–82.

    CAS  PubMed  Google Scholar 

  74. 74.

    Hicke L, Schubert HL, Hill CP. Ubiquitin-binding domains. Nat Rev Mol Cell Biol. 2005;6(8):610–21.

    CAS  PubMed  Google Scholar 

  75. 75.

    Mayer J, et al. E3 ubiquitin ligases. Essays Biochem. 2005;41:15–30.

    Google Scholar 

  76. 76.

    Nandi D, et al. The ubiquitin-proteasome system. J Biosci. 2006;31(1):137–55.

    CAS  PubMed  Google Scholar 

  77. 77.

    Hon W-C, et al. Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL. Nat. 2002;417(6892):975–8.

    CAS  Google Scholar 

  78. 78.

    Lin PH, Chiang MT, Chau LY. Ubiquitin–proteasome system mediates heme oxygenase-1 degradation through endoplasmic reticulum-associated degradation pathway. Biochimica et Biophysica Acta (BBA)-Mol Cell Res. 2008;1783(10): 1826–1834.

  79. 79.

    Meyer HH, Wang Y, Warren G. Direct binding of ubiquitin conjugates by the mammalian p97 adaptor complexes, p47 and Ufd1–Npl4. EMBO J. 2002;21(21):5645–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Yerlikaya A. Expression of heme oxygenase-1 in response to proteasomal inhibition. Protein Pept Lett. 2012;19(12):1330–3.

    CAS  PubMed  Google Scholar 

  81. 81.

    Dreger H, et al. Protection of vascular cells from oxidative stress by proteasome inhibition depends on Nrf2. Cardiovasc Res. 2010;85(2):395–403.

    CAS  PubMed  Google Scholar 

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Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran, and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran.

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Hemmati, M., Yousefi, B., Bahar, A. et al. Importance of Heme Oxygenase-1 in Gastrointestinal Cancers: Functions, Inductions, Regulations, and Signaling. J Gastrointest Canc (2021).

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  • Colorectal cancer
  • Heme oxygenase-1
  • Microbiota
  • Inflammatory
  • Autophagy