Роль гипоксии и транскрипционных факторов HIF в развитии язвенного колита и ассоциированного с ним колоректального рака

Одним из факторов, способствующих развитию колоректального рака, является воспаление. Хронический язвенный колит может быть причиной развития ассоциированного с ним колоректального рака (Colitis-Associated Colorectal cancer, CAC) в 1,6–3,7% случаев. Основным регулятором клеточного ответа на воспаление является белок NF-κB, который за счет наличия сайта связывания в соответствующем гене, индуцирует экспрессию и синтез транскрипционного фактора HIF-1α (Hypoxia-Inducible Factor 1α). Окислительный стресс, возникающий в ходе воспалительного процесса, зачастую приводит к возникновению мутаций в клетках. ДНК быстро пролиферирующих эпителиальных клеток толстой кишки становится мишенью для активных форм кислорода, что в итоге приводит к инициации и прогрессии опухолей. Темпы развития CAC во многом зависят от исходной устойчивости организма к гипоксии. У животных с низкой устойчивостью к гипоксии отмечаются более быстрые темпы инициации и прогрессии CAC по сравнению с высокоустойчивыми особями, что характеризуется более высокой частотой развития аденокарцином, высокими уровнями экспрессии генов Hif3a, Vegf, Tnfa, Il10, Tgfb, Cmet, Egf, Egfr, Bax, Muc1 и Cldn7 в опухолях, выраженными изменениями гематологических показателей и дисбалансом субпопуляций лимфоцитов в опухолях, брыжеечных лимфоузлах и крови. Понимание механизмов взаимосвязи устойчивости к гипоксии, активности HIF, особенностей течения хронических воспалительных и опухолевых процессов необходимо для разработки новых подходов к персонализированной терапии заболеваний, сопровождающихся недостатком кислорода.

1. Turizo-Smith A.D., Córdoba-Hernandez S., Mejía-Guarnizo L.V., Monroy-Camacho P.S., Rodríguez-Gar cía J.A. Inflammation and cancer: friend or foe? Front. Pharmacol. 2024;15:1385479.

2. Korniluk A., Koper O., Kemona H., Dymicka-Piekarska V. From inflammation to cancer. Ir. J. Med. Sci. 2017;186(1):57–62.

3. Siegfried G., Descarpentrie J., Evrard S., Khatib A.-M. Proprotein convertases: Key players in inflammation-related malignancies and metastasis. Cancer Lett. 2020;473:50–61.

4. Miftahussurur M., Yamaoka Y., Graham D.Y. Helicobacter pylori as an oncogenic pathogen, revisited. Expert Rev. Mol. Med. 2017;19:e4.

5. Kobayashi K., Tomita H., Shimizu M., Tanaka T., Suzui N., Miyazaki T., Hara A. p53 expression as a diagnostic biomarker in ulcerative colitis-associated cancer. Int. J. Mol. Sci. 2017;18(6):1284.

6. Shah S.C., Itzkowitz S.H. Colorectal cancer in inflammatory bowel disease: mechanisms and management. Gastroenterology. 2022;162(3):715-730.e3.

7. Keller D.S., Windsor A., Cohen R., Chand M. Colorectal cancer in inflammatory bowel disease: review of the evidence. Tech. Coloproctol. 2019;23(1):3–13.

8. Rogler G. Chronic ulcerative colitis and colorectal cancer. Cancer Lett. 2014;345(2):235–241.

9. Brackmann S., Andersen S.N., Aamodt G., Langmark F., Clausen O.P.F., Aadland E. Fausa O., Rydning A., Vatn M.H. Relationship between clinical parameters and the colitis-colorectal cancer interval in a cohort of patients with colorectal cancer in inflammatory bowel disease. Scand. J. Gastroenterol. 2009;44(1):46–55.

10. Behzadi P., García-Perdomo H.A., Karpiński T.M. Toll-like receptors: General molecular and structural biology. J. Immunol. Res. 2021;2021:9914854.

11. Liu T., Zhang L., Joo D., Sun S.-C. NF-κB sig naling in inflammation. Signal Transduct. Target Ther. 2017;2:17023.

12. Rius J., Guma M., Schachtrup C., Akassoglou K., Zinkernagel A.S., Nizet V. Johnson R.S., Haddad G.G., Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature. 2008;453(7196):807–811.

13. van Uden P., Kenneth N.S., Rocha S. Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem J. 2008;412(3):477–484.

14. van Uden P., Kenneth N.S., Webster R., Müller H.A., Mudie S., Rocha S. Evolutionary conserved regulation of HIF-1β by NF-κB. PLoS Genet. 2011;7(1):e1001285.

15. Dong S., Liang S., Cheng Z., Zhang X., Luo L., Li L., Zhang W., Li S., Xu Q., Zhong M., Zhu J., Zhang G., Hu S. ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer. J. Exp. Clin. Cancer Res. 2022;41(1):15.

16. Feng Z., Zhang S., Han Q., Chu T., Wang H., Yu L., Zhang W., Liu J., Liang W., Xue J., Wu X., Zhang C., Wang Y. Liensinine sensitizes colorectal cancer cells to oxaliplatin by targeting HIF-1α to inhibit autophagy. Phytomedicine. 2024;129:155647.

17. Guo J., Meng F., Hu R., Chen L., Chang J., Zhao K., Ren H., Liu Z., Hu P., Wang G., Tai J. Inhibition of the NF-κB/HIF-1α signaling pathway in colorectal cancer by tyrosol: a gut microbiota-derived metabolite. J. Immunother. Cancer. 2024;12(9):e008831.

18. Kirova Y.I., Germanova E.L., Lukyanova L.D. Phenotypic features of the dynamics of HIF-1α levels in rat neocortex in different hypoxia regimens. Bull. Exp. Biol. Med. 2013;154(6):718–722.

19. Dzhalilova D., Kosyreva A., Vishnyakova P., Zolotova N., Tsvetkov I., Mkhitarov V., Mikhailova L., Kakturskiy L., Makarova O.. Age-related differences in hypoxia-associated genes and cytokine profile in male Wistar rats. Heliyon. 2021;7(9):e08085.

20. Kosyreva A.M., Dzhalilova D.S., Makarova O.V., Tsvetkov I.S., Zolotova N.A., Diatroptova M.A., Ponomarenko E., Mkhitarov V., Khochanskiy D., Mikhailova L. Sex differences of inflammatory and immune response in pups of Wistar rats with SIRS. Sci. Rep. 2020;10(1):15884.

21. Dzhalilova D.S., Kosyreva A.M., Diatroptov M.E., Ponomarenko E.A., Tsvetkov I.S., Zolotova N.A., Mkhitarov V., Khochanskiy D., Makarova O.V. Dependence of the severity of the systemic inflammatory response on resistance to hypoxia in male Wistar rats. J. Inflamm. Res. 2019;12:73–86.

22. Dzhalilova D.S., Zolotova N.A., Polyakova M.A., Diatroptov M.E., Dobrynina M.T., Makarova O.V. Morphological features of the inflammatory process and subpopulation pattern of peripheral blood lymphocytes during chronic colitis in mice exhibiting different responses to hypoxia. Clin. Exp. Morphology. 2018;28(4):13–20.

23. Dzhalilova D.Sh., Polyakova M.A., Diatroptov M.E., Zolotova N.A., Makarova O.V. Morphological changes in the colon and composition of peripheral blood lymphocytes in acute colitis in mice with different resistance to hypoxia. Mol. Med. 2018;16(6):46–50.

24. Dzhalilova D.S., Silina M.V., Kosyreva A.M., Tsvetkov I.S., Makarova O.V. Morphological and molecular biological features of the systemic inflammatory response in old wistar rats with high and low resistance to hypoxia. Bull. Exp. Biol. Med. 2023;175(5):704–710.

25. Dzhalilova D.S., Silina M.V., Kosyreva A.M., Tsvet kov I.S., Makarova O.V. Comparative molecular and biological characteristic of the systemic inflammatory response in adult and old male Wistar rats with different resistance to hypoxia. Bull. Exp. Biol. Med. 2024;176(5):680–686.

26. Dzhalilova D.Sh., Tsvetkov I.S., Makarova O.V. Thymus morphological characteristics in acute and chronic colitis in animals with different hypoxia tolerance. Russ. J. Immunol. 2024;27(3):413–420.

27. Dzhalilova D.S., Zolotova N.A., Mkhitarov V.A., Kosyreva A.M., Tsvetkov I.S., Khalansky A.S., Alekseeva A.I., Fatkhudinov T.H., Makarova O.V. Morphological and molecular-biological features of glioblastoma progression in tolerant and susceptible to hypoxia Wistar rats. Sci. Rep. 2023;13(1):12694.

28. Fridman I.A., Ponomarenko E.A., Makarova O.V., Postovalova E.A., Zolotova N.A., Khochanskiy D.N., Mkhitarov V.A., Tsvetkov I.S., Kosyreva A.M. Morphological characteristic of melanoma B16 progression in C57BL/6 mice with high and low resistance to hypoxia. Bull. Exp. Biol. Med. 2020;168(3):390–394.

29. Dzhalilova D.S., Silina M.V., Zolotova N.A., Portnova T.S., Vagabov M.D., Tsvetkov I.S., Makarova O.V. Morphological characteristics of colon tumors in mice with different tolerance to hypoxia. Bull. Exp. Biol. Med. 2024;177(1):162–168.

30. Dzhalilova D., Silina M., Kosyreva A., Fokichev N., Makarova O. Morphofunctional changes in the immune system in colitis-associated colorectal cancer in tolerant and susceptible to hypoxia mice. PeerJ. 2025;13:e19024.

31. Lan T., Chen L., Wei X. Inflammatory cytokines in cancer: comprehensive understanding and clinical progress in gene therapy. Cells. 2021;10(1):100.

32. Murata M. Inflammation and cancer. Environ. Health Prev. Med. 2018;23(1):50.

33. Fan Y., Mao R., Yang J. NF-κB and STAT3 signa ling pathways collaboratively link inflammation to cancer. Protein Cell. 2013;4(3):176–185.

34. Odenwald M.A., Turner J.R. The intestinal epithelial barrier: a therapeutic target? Nat. Rev. Gastroenterol. Hepatol. 2017;14(1):9–21.

35. Hardbower D.M., Coburn L.A., Asim M., Singh K., Sierra J.C., Barry D.P., Gobert A.P., Piazuelo M.B., Washington M.K., Wilson K.T. EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis. Oncogene. 2017;36(27):3807–3819.

36. Wang Z., Chang Y., Sun H., Li Y., Tang T. Advances in molecular mechanisms of inflammatory bowel disease-associated colorectal cancer (Review). Oncol. Lett. 2024;27(6):257.

37. Whiteside T.L. The role of regulatory T cells in cancer immunology. Immunotargets Ther. 2015;4:159–171.

38. Whiteside T.L. NK cells in the tumor microenvironment and thioredoxin activity. J. Clin. Invest. 2020;130(10):5115–5117.

39. Whiteside T.L. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008;27(45):5904–5912.

40. Khan S.U., Khan M.U., Azhar Ud.Din.M., Khan I.M., Khan M.I., Bungau S., Hassan S.S.U. Reprogramming tumor-associated macrophages as a unique approach to target tumor immunotherapy. Front. Immunol. 2023;14:1166487.

41. Yang H., Zhang Q., Xu M., Wang L., Chen X., Feng Y., Li Y., Zhang X., Cui W., Jia X.. CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Mol. Cancer. 2020;19(1):41.

42. Chen Y., Song Y., Du W., Gong L., Chang H., Zou Z. Tumor-associated macrophages: an accomplice in solid tumor progression. J. Biomed. Sci. 2019;26(1):78.

43. Onizawa M., Nagaishi T., Kanai T., et al. Signa ling pathway via TNF-alpha/NF-kappaB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis. Am. J. Physiol. Gastrointest. Liver Physiol. 2009;296(4):G850–G859.

44. Wang X., Lin Y. Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol. Sin. 2008;29(11):1275–1288.

45. Bassiouni W., Ali M.A.M., Schulz R. Multifunctional intracellular matrix metalloproteinases: implications in disease. FEBS J. 2021;288(24):7162–7182.

46. Nabors L.B., Suswam E., Huang Y., Yang X., Johnson M.J., King P.H. Tumor necrosis factor alpha induces angiogenic factor up-regulation in malignant glioma cells: a role for RNA stabilization and HuR. Cancer Res. 2003;63(14):4181–4187.

47. Tomita Y., Yang X., Ishida Y., Nemoto-Sasaki Y., Kondo T., Oda M., Watanabe G., Chaldakov G.N., Fujii C., Mukaida N. Spontaneous regression of lung metastasis in the absence of tumor necrosis factor receptor p55. Int. J. Cancer. 2004;112(6):927–933.

48. Zou H., Li R., Hu H., Hu Y., Chen X. Modulation of regulatory T cell activity by TNF receptor type II-targeting pharmacological agents. Front. Immunol. 2018;9:594.

49. Singh N., Baby D., Rajguru J.P., Patil P.B., Thakkannavar S.S., Pujari V.B. Inflammation and cancer. Ann. Afr. Med. 2019;18(3):121–126.

50. Ahmad N., Ammar A., Storr S.J., Green A.R., Rakha E., Ellis I.O., Martin S.G. IL-6 and IL-10 are associa ted with good prognosis in early stage invasive breast cancer patients. Cancer Immunol Immunother. 2018;67(4):537–549.

51. Saxena N.K., Vertino P.M., Anania F.A., Sharma D. leptin-induced growth stimulation of breast cancer cells involves recruitment of histone acetyltransferases and mediator complex to CYCLIN D1 promoter via activation of Stat3. J. Biol. Chem. 2007;282(18):13316–13325.

52. Braun D.A., Fribourg M., Sealfon S.C. Cytokine response is determined by duration of receptor and signal transducers and activators of transcription 3 (STAT3) activation. J. Biol. Chem. 2013;288(5):2986–2993.

53. Qu Z., Sun F., Zhou J., Li L., Shapiro S.D., Xiao G. Interleukin-6 prevents the initiation but enhances the progression of lung cancer. Cancer Res. 2015;75(16):3209–3215.

54. Yin Y., Wan J., Yu J., Wu K. Molecular pathogenesis of colitis-associated colorectal cancer: immunity, gene tics, and intestinal microecology. Inflamm. Bowel Dis. 2023;29(10):1648–1657.

55. Fearon E.R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–767.

56. Scarpa M., Scarpa M., Castagliuolo I., Erroi F., Kotsafti A., Basato S., Brun P., D’Incà R., Rugge M., Angriman I., Castoro C. Aberrant gene methylation in non-neoplastic mucosa as a predictive marker of ulcerative colitis-associated CRC. Oncotarget. 2016;7(9):10322–10331.

57. Emmett R.A., Davidson K.L., Gould N.J., Arasa radnam R.P. DNA methylation patterns in ulcerative colitis-associated cancer: a systematic review. Epigenomics. 2017;9(7):1029–1042.

58. Bocchetti M., Ferraro M.G., Ricciardiello F., Ottaiano A., Luce A., Cossu A.M., Scrima M., Leung W.Y., Abate M., Stiuso P., Caraglia M., Zappavigna S., Yau T.O. The role of microRNAs in development of colitis-associated colorectal cancer. Int. J. Mol. Sci. 2021;22(8):3967.

59. Jaakkola P., Mole D.R., Tian Y.M., Wilson M.I., Gielbert J., Gaskell S.J., von Kriegsheim A., Hebestreit H.F., Mukherji M., Schofield C.J., Maxwell P.H., Pugh C.W., Ratcliffe P.J. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468–472.

60. Haase V.H. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial. Int. 2017;21 Suppl. 1(Suppl. 1):S110–S124.

61. Maxwell P.H., Wiesener M.S., Chang G.W., Clifford S.C., Vaux E.C., Cockman M.E., Wykoff C.C., Pugh C.W., Maher E.R., Ratcliffe P.J. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–275.

62. Ivan M., Kondo K., Yang H., Kim W., Valiando J., Ohh M., Salic A., Asara J.M., Lane W.S., Kaelin Jr W.G.. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464–468.

63. Duan C. Hypoxia-inducible factor 3 biology: complexities and emerging themes. Am. J. Physiol. Cell Physiol. 2016;310(4):C260–C269.

64. Jaskiewicz M., Moszynska A., Serocki M., Króli czewski J., Bartoszewska S., Collawn J.F., Bartoszewski R. Hypoxia-inducible factor (HIF)-3a2 serves as an endothelial cell fate executor during chronic hypoxia. EXCLI J. 2022;21:454–469.

65. Silina M.V., Dzhalilova D.S., Makarova O.V. Role of MicroRNAs in regulation of cellular response to hypoxia. Biochemistry (Mosc.). 2023;88(6):741–757.

66. Lee P., Chandel N.S., Simon M.C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat. Rev. Mol. Cell Biol. 2020;21(5):268–283.

67. Sebestyén A., Kopper L., Dankó T., Tímár J. Hypoxia signaling in cancer: from basics to clinical practice. Pathol Oncol Res. 2021;27:1609802.

68. Korbecki J., Simińska D., Gąssowska-Dobrowolska M., Listos J., Gutowska I., Chlubek D., Baranowska-Bosiacka I. Chronic and cycling hypoxia: Drivers of cancer chronic inflammation through HIF-1 and NF-κB activation: A review of the molecular mechanisms. Int. J. Mol. Sci. 2021;22(19):10701.

69. Hellwig-Bürgel T., Rutkowski K., Metzen E., Fandrey J., Jelkmann W. Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1. Blood. 1999;94(5):1561–1567.

70. Tannahill G.M., Curtis A.M., Adamik J., et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013;496(7444):238–242.

71. Sharma V., Dixit D., Koul N., Mehta V.S., Sen E. Ras regulates interleukin-1β-induced HIF-1α transcriptio nal activity in glioblastoma. J. Mol. Med. 2011;89(2):123–136.

72. Malkov M.I., Lee C.T., Taylor C.T. Regulation of the hypoxia-inducible factor (HIF) by pro-inflammatory cytokines. Cells. 2021;10(9):2340.

73. Koivunen P., Hirsilä M., Günzler V., Kivirikko K.I., Myllyharju J. Catalytic properties of the asparaginyl hydro xylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J. Biol. Chem. 2004;279(11):9899–9904.

74. Jantsch J., Wiese M., Schödel J., Castiglione K., Gläsner J., Kolbe S., Mole D., Schleicher U., Eckardt K.U., Hensel M., Lang R., Bogdan C., Schnare M., Willam C. Toll-like receptor activation and hypoxia use distinct signaling pathways to stabilize hypoxia-inducible factor 1α (HIF1A) and result in differential HIF1A-dependent gene expression. J. Leukoc. Biol. 2011;90(3):551–562.

75. Peyssonnaux C., Cejudo-Martin P., Doedens A., Zinkernagel A.S., Johnson R.S., Nizet V. Cutting edge: Essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis. J. Immunol. 2007;178(12):7516–7519.

76. Silina M.V., Dzhalilova D.S., Diatroptova M.A., Grin O.O., Babaev M.A., Makarova O.V. Differences in the blood levels of HIF-1α and VNN1 and expression of HIF1A and NFKB1 in leukocytes in cardiological patients with risk of postoperative complications. Bull. Exp. Biol. Med. 2025:178(6):691–696.

77. Karhausen J., Furuta G.T., Tomaszewski J.E., Johnson R.S., Colgan S.P., Haase V.H. Epithelial hypoxiainducible factor-1 is protective in murine experimental colitis. J. Clin. Invest. 2004;114(8):1098–1106.

78. Cummins E.P., Seeballuck F., Keely S.J., Mangan N.E., Callanan J.J., Fallon P.G., Taylor C.T. The hydro xylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology. 2008;134(1):156–165.

79. Manresa M.C., Taylor C.T. Hypoxia inducible factor (HIF) hydroxylases as regulators of intestinal epithelial barrier function. Cell. Mol. Gastroenterol. Hepatol. 2017;3(3):303–315.

80. Brown E., Taylor C.T. Hypoxia-sensitive pathways in intestinal inflammation. J. Physiol. (Lond.). 2018;596(15):2985–2989.

81. Dvornikova K.A., Platonova O.N., Bystrova E.Y. Hypoxia and intestinal inflammation: common molecular mechanisms and signaling pathways. Int. J. Mol. Sci. 2023;24(3):2425.

82. Barbi J., Pardoll D., Pan F. Metabolic control of the Treg/Th17 axis. Immunol. Rev. 2013;252(1):52–77.

83. Pazmandi J., Kalinichenko A., Ardy R.C., Boztug K. Early-onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms. Immunol. Rev. 2019;287(1):162–185.

84. Sukumar M., Liu J., Ji Y., et al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Invest. 2013;123(10):4479–4488.

85. Sun M., He C., Wu W., Zhou G., Liu F., Cong Y., Liu Z. Hypoxia inducible factor-1α-induced interleukin-33 expression in intestinal epithelia contributes to mucosal homeostasis in inflammatory bowel disease. Clin. Exp. Immunol. 2017;187(3):428–440.

86. Monticelli L.A., Osborne L.C., Noti M., Tran S.V., Zaiss D.M.W., Artis D. IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions. Proc. Natl. Acad. Sci. U.S.A. 2015;112(34):10762–10767.

87. Bäcker V., Cheung F.-Y., Siveke J.T., Fandrey J., Winning S. Knockdown of myeloid cell hypoxia-inducible factor-1α ameliorates the acute pathology in DSS-induced colitis. PLoS One. 2017;12(12):e0190074.

88. Cramer T., Yamanishi Y., Clausen B.E., Förster I., Pawlinski R., Mackman N., Haase V.H., Jaenisch R., Corr M., Nizet V., Firestein G.S., Gerber H.P., Ferrara N., Johnson R.S. HIF-1alpha is essential for myeloid cellmediated inflammation. Cell. 2003;112(5):645–657.

89. Scheerer N., Dehne N., Stockmann C., Swoboda S., Baba H.A., Neugebauer A., Johnson R.S., Fandrey J. Myeloid hypoxia-inducible factor-1α is essential for skeletal muscle regeneration in mice. J. Immunol. 2013;191(1):407–414.

90. Flück K., Breves G., Fandrey J., Winning S. Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis. Mucosal. Immunol. 2016;9(2):379–390.

91. Triner D., Xue X., Schwartz A.J., Jung I., Colacino J.A., Shah Y.M. Epithelial hypoxia-inducible factor 2α facilitates the progression of colon tumors through recruiting neutrophils. Mol. Cell. Biol. 2017;37(5):e00481-16.

92. Kerber E.L., Padberg C., Koll N., Schuetzhold V., Fandrey J., Winning S. The importance of hypoxia-inducible factors (HIF-1 and HIF-2) for the pathophysiology of inflammatory bowel disease. Int. J. Mol. Sci. 2020;21(22):8551.

93. Dzhalilova D.S., Makarova O.V. HIF-dependent mechanisms of relationship between hypoxia tolerance and tumor development. Biochemistry (Mosc.). 2021;86(10):1163–1180.

94. Jain K., Suryakumar G., Prasad R., Ganju L. Upregulation of cytoprotective defense mechanisms and hypoxia-responsive proteins imparts tolerance to acute hypobaric hypoxia. High Alt. Med. Biol. 2013;14(1):65–77.

95. Belosludtsev K.N., Dubinin M.V., Talanov E.Y., Starinets V.S., Tenkov K.S., Zakharova N.M., Belosludtseva N.V. Transport of Ca2+ and Ca2+-dependent permeability transition in the liver and heart mitochondria of rats with diffe rent tolerance to acute hypoxia. Biomolecules. 2020;10(1):114.

96. Glazachev O.S., Geppe N.A., Timofeev Yu.S., Samartseva V.G., Dudnik E.N., Zapara M.A., Chebysheva S.N. Indicators of individual hypoxia resistance – a way to optimize hypoxic training for children. Ross. Vestn. Perinatol. Pediatr. 2020;65(4):78–84.

97. Lu H., Wang R., Li W., Xie H., Wang C., Hao Y., Sun Y., Jia Z. Plasma cytokine profiling to predict susceptibility to acute mountain sickness. Eur. Cytokine Netw. 2016;27(4):90–96.

98. Soree P., Gupta R.K., Singh K., Desiraju K., Agrawal A., Vats P., Bharadwaj A., Baburaj T.P., Chaudhary P., Singh V.K., Verma S., Bajaj A.C., Singh S.B. Raised HIF1α during normoxia in high altitude pulmonary edema susceptible non-mountaineers. Sci. Rep. 2016;6:26468.

99. Urakov A., Urakova N., Gurevich K., Muhutdinov N. Cardiology, respiratory failure, and tolerance of hypoxia in the context of COVID-19: a multidisciplinary perspective. Rev. Cardiovasc. Med. 2022;23(1):21.

100. Ioannou M., Paraskeva E., Baxevanidou K., Simos G., Papamichali R., Papacharalambous C., Samara M., Koukoulis G. HIF-1α in colorectal carcinoma: review of the literature. J. BUON. 2015;20(3):680–689.

101. Däster S., Amatruda N., Calabrese D., Ivanek R., Turrini E., Droeser R.A., Zajac P., Fimognari C., Spagnoli G.C., Iezzi G., Mele V., Muraro M.G. Induction of hypoxia and necrosis in multicellular tumor spheroids is associated with resistance to chemotherapy treatment. Oncotarget. 2017;8(1):1725–1736.

102. Riffle S., Hegde R.S. Modeling tumor cell adaptations to hypoxia in multicellular tumor spheroids. J. Exp. Clin. Cancer Res. 2017;36(1):102.

103. Sorokin M., Buzdin A.A., Guryanova A., et al. Large-scale assessment of pros and cons of autopsy-derived or tumor-matched tissues as the norms for gene expression analysis in cancers. Comput. Struct. Biotechnol. J. 2023;21:3964–3986.

104. Semenza G.L. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol. Med. 2002;8(4 Suppl.):S62–S67.

105. Heldin C.-H., Rubin K., Pietras K., Ostman A. High interstitial fluid pressure – an obstacle in cancer therapy. Nat. Rev. Cancer. 2004;4(10):806–813.

106. Siemann D.W. The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents. Cancer Treat. Rev. 2011;37(1):63–74.

107. Yu T., Tang B., Sun X. Development of Inhibitors targeting hypoxia-inducible factor 1 and 2 for cancer therapy. Yonsei Med. J. 2017;58(3):489–496.

108. Semenza G.L. Defining the role of hypoxiainducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29(5):625–634.

109. Jun J.C., Rathore A., Younas H., Gilkes D., Polotsky V.Y. Hypoxia-inducible factors and cancer. Curr. Sleep Med. Rep. 2017;3(1):1–10.

110. Markov D., Poryazova E., Raycheva R., Mar kov G. Expression of HIF-1α, Ki67, SMA and E-cadherin in endometriosis, endometrial and ovarian carcinoma. Folia Med. (Plovdiv.). 2024;66(1):97–103.

111. Yang Y., Wu J., Zhu H., Shi X., Liu J., Li Y., Wang M. Effect of hypoxia-HIF-1α-periostin axis in thyroid cancer. Oncol. Rep. 2024;51(4):57.

112. Hao B., Dong H., Xiong R., Song C., Xu C., Li N., Geng Q. Identification of SLC2A1 as a predictive biomarker for survival and response to immunotherapy in lung squamous cell carcinoma. Comput. Biol. Med. 2024;171:108183.

113. S V., Balasubramanian S., Perumal E., Santhakumar K. Identification of key genes and signalling pathways in clear cell renal cell carcinoma: An integrated bioinformatics approach. Cancer Biomark. 2024;40(1):111–123.

114. Mahapatra N., Panda A., Dash K., Bhuyan L., Mishra P., Mohanty A. The study of expression of hypoxiainducible factor-1 alpha (HIF-1 alpha) and hypoxiainducible factor-2 alpha (HIF-2 alpha) in oral squamous cell carcinoma: An immunohistochemical study. Cureus. 2023;15(9):e45189.

115. Flamme I., Krieg M., Plate K.H. Up-regulation of vascular endothelial growth factor in stromal cells of hemangioblastomas is correlated with up-regulation of the transcription factor HRF/HIF-2alpha. Am. J. Pathol. 1998;153(1):25–29.

116. Giatromanolaki A., Koukourakis M.I., Sivridis E., Turley H., Talks K., Pezzella F., Gatter K.C., Harris A.L. Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/mole cular profile of tumours and survival. Br. J Cancer. 2001;85(6):881–890.

117. Garcia Garcia C.J., Huang Y., Fuentes N.R., et al. Stromal HIF2 regulates immune suppression in the pancreatic cancer microenvironment. Gastroenterology. 2022;162(7):2018–2031.

118. Contenti J., Guo Y., Larcher M., et al. HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma. BioRxiv. 2023;10(1):338.

119. Liu J., Jiang Y., Chen L., Qian Z., Zhang Y. Associations between HIFs and tumor immune checkpoints: mechanism and therapy. Discov. Oncol. 2024;15(1):2.

120. Zhang R., Zhao J., Zhao L. EPAS1/HIF-2α acts as an unanticipated tumor-suppressive role in papillary thyroid carcinoma. Int. J. Gen. Med. 2023;16:2165–2174.

121. Burtscher M., Mairer K., Wille M., Gatterer H., Ruedl G., Faulhaber M., Summan G. Short-term exposure to hypoxia for work and leisure activities in health and disease: which level of hypoxia is safe? Sleep Breath. 2012;16(2):435–442.

122. Maynard M.A., Evans A.J., Shi W., Kim W.Y., Liu F.-F., Ohh M. Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression. Cell Cycle. 2007;6(22):2810–2816.

123. Silakit R., Kitirat Y., Thongchot S., Loilome W., Techasen A., Ungarreevittaya P., Khuntikeo N., Yongva nit P., Yang J.H., Kim N.H., Yook J.I., Namwat N. Potential role of HIF-1-responsive microRNA210/HIF3 axis on gemcitabine resistance in cholangiocarcinoma cells. PLoS One. 2018;13(6):e0199827.

124. Knechtel G., Szkandera J., Stotz M., Hofmann G., Langsenlehner U., Krippl P.. Single nucleotide polymorphisms in the hypoxia-inducible factor-1 gene and colorectal cancer risk. Mol. Carcinog. 2010;49(9):805–809.

125. Islam F., Gopalan V., Lu C.T., Pillai S., Lam A.K. Identification of novel mutations and functional impacts of EPAS1 in colorectal cancer. Cancer Med. 2021;10(16):5557–5573.

126. Rohwer N., Cramer T. Hypoxia-mediated drug resis tance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist. Updat. 2011;14(3):191–201.

127. Wei T.-T., Lin Y.-T., Tang S.-P., Luo C.-K., Tsai C.-T., Shun C.-T., Chen C.-C. Metabolic targeting of HIF-1α potentiates the therapeutic efficacy of oxaliplatin in colorectal cancer. Oncogene. 2020;39(2):414–427.

128. Rasheed S., Harris A.L., Tekkis P.P., Turley H., Silver A., McDonald P.J., Talbot I.C., Glynne-Jones R., Northover J.M., Guenther T. Hypoxia-inducible factor-1alpha and -2alpha are expressed in most rectal cancers but only hypoxia-inducible factor-1alpha is associated with prognosis. Br. J. Cancer. 2009;100(10):1666–1673.

129. Schmitz K.J., Müller C.I., Reis H., Alakus H., Winde G., Baba H.A., Wohlschlaeger J., Jasani B., Fandrey J., Schmid K.W. Combined analysis of hypoxia-inducible factor 1 alpha and metallothionein indicates an aggressive subtype of colorectal carcinoma. Int. J. Colorectal. Dis. 2009;24(11):1287–1296.

130. Rajaganeshan R., Prasad R., Guillou P.J., Scott N., Poston G., Jayne D.G. Expression patterns of hypoxic mar kers at the invasive margin of colorectal cancers and liver metastases. Eur. J. Surg. Oncol. 2009;35(12):1286–1294.

131. Yoshimura H., Dhar D.K., Kohno H., Kubota H., Fujii T., Ueda S., Kinugasa S., Tachibana M., Nagasue N. Prognostic impact of hypoxia-inducible factors 1alpha and 2alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression. Clin. Cancer Res. 2004;10(24):8554–8560.

132. Kuwai T., Kitadai Y., Tanaka S., Onogawa S., Matsutani N., Kaio E., Ito M., Chayama K. Expression of hypoxia-inducible factor-1alpha is associated with tumor vascularization in human colorectal carcinoma. Int. J. Cancer. 2003;105(2):176–181.

133. Furlan D., Sahnane N., Carnevali I., Cerutti R., Bertoni F., Kwee I., Uccella S., Bertolini V., Chiaravalli A.M., Capella C. Up-regulation of the hypoxia-inducible factor-1 transcriptional pathway in colorectal carcinomas. Hum. Pathol. 2008;39(10):1483–1494.

134. Ren J., Sui H., Fang F., Li Q., Li B. The application of ApcMin/+ mouse model in colorectal tumor researches. J. Cancer Res. Clin. Oncol. 2019;145(5):1111–1122.

135. Xue X., Taylor M., Anderson E., Hao C., Qu A., Greenson J.K., Zimmermann E.M., Gonzalez F.J., Shah Y.M. Hypoxia-inducible factor-2α activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res. 2012;72(9):2285–2293.

136. Shah Y.M., Matsubara T., Ito S., Yim S.-H., Gonzalez F.J. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 2009;9(2):152–164.

137. Nelson R.L. Iron and colorectal cancer risk: human studies. Nutr. Rev. 2001;59(5):140–148.

138. Seril D.N., Liao J., Ho K.-L.K., Warsi A., Yang C.S., Yang G.-Y. Dietary iron supplementation enhances DSS-induced colitis and associated colorectal carcinoma development in mice. Dig. Dis. Sci. 2002;47(6):1266–1278.

139. Chen Z., He X., Xia W., Huang Q., Zhang Z., Ye J., Ni C., Wu P., Wu D., Xu J., Qiu F., Huang J. Prognostic value and clinicopathological differences of HIFs in colorectal cancer: evidence from meta-analysis. PLoS One. 2013;8(12):e80337.

140. Baba Y., Nosho K., Shima K., Irahara N., Chan A.T., Meyerhardt J.A., Chung D.C., Giovannucci E.L., Fuchs C.S., Ogino S. HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am. J. Pathol. 2010;176(5):2292–2301.

141. Xue X., Jungles K., Onder G., Samhoun J., Győrffy B., Hardiman K.M. HIF-3α1 promotes colorectal tumor cell growth by activation of JAK-STAT3 signaling. Oncotarget. 2016;7(10):11567–11579.

142. Villareal L.B., Falcon D.M., Xie L., Xue X. Hypoxia-inducible factor 3α1 increases epithelial-to-mesenchymal transition and iron uptake to drive colorectal cancer liver metastasis. Br. J. Cancer. 2024;130(12):1904–1915.

143. Jain K., Suryakumar G., Prasad R., Ganju L. Differential activation of myocardial ER stress response: a possible role in hypoxic tolerance. Int. J. Cardiol. 2013;168(5):4667–4677.

144. Jain K., Suryakumar G., Ganju L., Singh S.B. Differential hypoxic tolerance is mediated by activation of heat shock response and nitric oxide pathway. Cell Stress Chaperones. 2014;19(6):801–812.

145. Dzhalilova D., Makarova O. Differences in tolerance to hypoxia: Physiological, biochemical, and molecular-biological characteristics. Biomedicines. 2020;8(10):428.

146. Dzhalilova D, Silina M, Tsvetkov I, Kosyreva A, Zolotova N, Gantsova E, Kirillov V., Fokichev N., Makarova O. Changes in the expression of genes regulating the response to hypoxia, inflammation, cell cycle, apoptosis, and epithelial barrier functioning during colitis-associated colorectal cancer depend on individual hypoxia tolerance. Int. J. Mol. Sci. 2024;25(14):7801.

147. Dai S., Zeng H., Liu Z., et al. Intratumoral CXCL13+CD8+T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma. J. Immunother. Cancer. 2021;9(2):e001823.

148. Yun S.-M., Kim S.-H., Kim E.-H. The molecular mechanism of transforming growth factor-β signaling for intestinal fibrosis: A mini-review. Front. Pharmacol. 2019;10:162.

149. Saraiva M., O’Garra A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 2010;10(3):170–181.

150. Navab R., Liu J., Seiden-Long I., et al. Cooverexpression of Met and hepatocyte growth factor promotes systemic metastasis in NCI-H460 non-small cell lung carcinoma cells. Neoplasia. 2009;11(12):1292–1300.

151. Ghosh P., Beas A.O., Bornheimer S.J., Garcia-Marcos M., Forry E.P., Johannson C., Ear J., Jung B.H., Cabrera B., Carethers J.M., Farquhar M.G. A G{alpha} i-GIV molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate. Mol. Biol. Cell. 2010;21(13):2338–2354.

152. Khodapasand E., Jafarzadeh N., Farrokhi F., Kamalidehghan B., Houshmand M. Is Bax/Bcl-2 ratio considered as a prognostic marker with age and tumor location in colorectal cancer? Iran Biomed. J. 2015;19(2):69–75.