ГИАЛУРОНОВАЯ КИСЛОТА: РОЛЬ В КЛЕТОЧНОМ ЦИКЛЕ

DOI: https://doi.org/10.29296/24999490-2020-04-03

В.Н. Хабаров(1), кандидат химических наук, Н.Н. Белушкина(2), доктор биологических наук, профессор, М.А. Пальцев(2), академик РАН, профессор, И.М. Кветной(3), доктор медицинских наук, профессор 1-АНО «Научно-исследовательский центр гиалуроновой кислоты», Российская Федерация, 119146, Москва, Комсомольский пр-т., 38/16; 2-Биологический факультет ФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова», Российская Федерация, 119234, Москва, Ленинские горы, д. 1, стр. 12; 3-ФГБУ «Санкт-Петербургский научно-исследовательский институт фтизиопульмонологии» МЗ РФ, Российская Федерация, 191036, Санкт-Петербург, Лиговский пр., д. 2–4 E-mail: igor.kvetnoy@yandex.ru

В обзоре рассмотрена система гиалуроновой кислоты (ГК), представленная ферментами синтеза (гиалуронансинтазы), расщепления (гиалуронидазы) и ее рецепторами. Продемонстрировано участие системы гиалуроновой кислоты в регуляции клеточного цикла. Важнейшим рецептором ГК является трансмембранный белок CD44, внутриклеточный домен которого связан с белками цитоскелета. Все компоненты системы ГК являются важными участниками клеточного цикла нормальных и, в еще большей степени, предраковых и раковых клеток. Продемонстрированы различия в регуляции клеточного цикла высокомолекулярными и низкомолекулярными фракциями ГК. Высокомолекулярная ГК поддерживает дифференцированные и стволовые клетки в фазе клеточного цикла G0, блокируя доступ к рецепторам. В процессе эмбриогенеза высокомолекулярная ГК активирует PI3K-АКТ и RAS-ERK каскады в первичных трофобластах, что приводит к их активной пролиферации. На пролиферацию клеток взрослого организма высокомолекулярная ГК оказывает противоположный, ингибирующий эффект за счет ингибирующего воздействия белка мерлин. Низкомолекулярная ГК и ГК-рецепторы вовлекаются в процессы клеточного цикла после его первичной инициации провоспалительными факторами. Для активации с помощью низкомолекулярной ГК цитоплазматического домена CD44 необходимо отсоединение от него белка мерлина. Использование ГК в медицинской практике требует полного учета этих разнообразных режимов регуляции.
Ключевые слова: 
гиалуроновая кислота

Список литературы: 
  1. Хабаров В.Н., Бойков П.Я., Селянин М.А. Гиалуроновая кислота. М.: Практическая медицина, 2012; 224. [Habarov V.N., Bojkov P.YA., Selyanin M.A. Hyaluronic acid. M.: Prakticheskaya medicina, 2012; 224 (in Russian)]
  2. Хабаров В.Н., Бойков П.Я. Биохимия гиалуроновой кислоты. М.: Тисо-принт, 2016; 288. [Habarov V.N., Bojkov P.YA., Selyanin M.A. Biochemistry of hyaluronic acid. M.: Tiso-print, 2016; 288 (in Russian)]
  3. Хабаров В.Н., Иванов П.Л. Биомедицинское применение гиалуроновой кислоты и ее химически модифицированных производных. М.: ГЭОТАР-МЕД, 2019; 288. [Habarov V.N., Ivanov P.L. Biomedical application of hyaluronic acid and its chemically modified derivatives. M.: GEOTAR-MED, 2019; 288 (in Russian)]
  4. Johnson P., Arif A.A., Lee-Sayer S.S.M., Dong Y. Hyaluronan and its interactions with immune cells in the healthy and inflamed lung. Front Immunol. 2018; 9: 2787. https://doi.org/10.3389/fimmu.2018.02787
  5. Krolikoski M., Monslow J., Puré E. The CD44-HA axis and inflammation in atherosclerosis: A temporal perspective. Matrix Biol. 2019; 78/79: 201–18. https://doi.org/10.1016/j.matbio.2018.05.007
  6. Liu R., Sun R., Zhang L., Zhang Q., Chen D., Zhong J., Xiao J. Hyaluronic acid enhances proliferation of human amniotic mesenchymal stem cells through activation of Wnt/β-catenin signaling pathway. Exp. Cell. Res. 2016; 345 (2): 218–29. https://doi.org/10.1016/j.yexcr.2016.05.019
  7. Chen X., Du Y., Liu Y., He Y., Zhang G., Yang C., Gao F. Hyaluronan arrests human breast cancer cell growth by prolonging the G0/G1 phase of the cell cycle. Acta Biochim Biophys Sin (Shanghai). 2018; 50 (12): 1181–89. https://doi.org/10.1093/abbs/gmy126
  8. Itano N., Kimata K. Mammalian hyaluronan synthases. IUBMB Life. 2002; 54 (4): 195–9. https://doi.org/10.1080/15216540214929
  9. Vigetti D., Viola M., Karousou E., De Luca G., Passi A. Metabolic control of hyaluronan synthases. Matrix Biol. 2014; 35: 8–13. https://doi.org/10.1016/j.matbio.2013.10.002
  10. Ohtsuki T., Asano K., Inagaki J., Shinaoka A., Kumagishi-Shinaoka K., Cilek M., Hatipoglu O., Oohashi T., Nishida K., Komatsubara I., Hirohata S. High molecular weight hyaluronan protects cartilage from degradation by inhibiting aggrecanase expression. J. Orthop Res. 2018; 36 (12): 3247–55. https://doi.org/10.1002/jor.24126
  11. Cowman M., Shortt C., Arora S., Fu Y., Villavieja J., Rathore J., Huang X., Rakshit T., Jung G., Kirsch T. Role of Hyaluronan in Inflammatory Effects on Human Articular Chondrocytes. Inflammation. 2019; 42 (5): 1808–20. https://doi.org/10.1007/s10753-019-01043-9
  12. Nagy N., Sunkari V.G., Kaber G., Hasbun S., Lam D.N., Speake C., Sanda S., McLaughlin T.L., Wight T., Long S., Bollyky P. Hyaluronan levels are increased systemically in human type 2 but not type 1 diabetes independently of glycemic control. Matrix Biol. 2019; 80: 46–58. https://doi.org/10.1016/j.matbio.2018.09.003
  13. Törrönen K., Nikunen K., Kärnä R., Tammi M., Tammi R., Rilla K. Tissue distribution and subcellular localization of hyaluronan synthase isoenzymes. Histochem Cell Biol. 2014; 141 (1): 17–31. https://doi.org/10.1007/s00418-013-1143-4
  14. Stuhlmeier K., Pollaschek C. Differential effect of transforming growth factor beta (TGF-beta) on the genes encoding hyaluronan synthases and utilization of the p38 MAPK pathway in TGF-beta-induced hyaluronan synthase 1 activation. J. Biol Chem. 2004; 279: 8753–60. https://doi.org/10.1074/jbc.M303945200
  15. Rauhala L., Jokela T., Kärnä R., Bart G., Takabe P., Oikari S., Tammi M., Pasonen-Seppänen S., Tammi R. Extracellular ATP activates hyaluronan synthase 2 (HAS2) in epidermal keratinocytes via P2Y2, Ca2+ signaling, and MAPK pathways. Biochem J. 2018; 475 (10): 1755–72. https://doi.org/10.1042/BCJ20180054
  16. Buhren B., Schrumpf H., Hoff N., Bölke E., Gerber P. Hyaluronidase: from clinical applications to molecular and cellular mechanisms. Eur. J. Med. Res. 2016; 21: 5. https://doi.org/10.1186/s40001-016-0201-5
  17. Hida D., Danielson B., Knudson C., Knudson W. CD44 knock-down in bovine and human chondrocytes results in release of bound HYAL2. Matrix Biol. 2015; 48: 42. https://doi.org/10.1016/j.matbio.2015.04.002
  18. Terazawa S., Nakajima H., Tobita K., Imokawa G. The decreased secretion of hyaluronan by older human fibroblasts under physiological conditions is mainly associated with the down-regulated expression of hyaluronan synthases but not with the expression levels of hyaluronidases. Cytotechnology. 2015; 67: 609–20. https://doi.org/10.1007/s10616-014-9707-2
  19. Qu C., Rilla K., Tammi R., Tammi M., Kröger H., Lammi M. Extensive CD44-dependent hyaluronan coats on human bone marrow-derived mesenchymal stem cells produced by hyaluronan synthases HAS1, HAS2 and HAS3. Int J. Biochem Cell Biol. 2014; 48: 45–54. https://doi.org/10.1016/j.biocel.2013.12.016
  20. Knudson W., Ishizuka S., Terabe K., Askew E., Knudson C. The pericellular hyaluronan of articular chondrocytes. Matrix Biol. 2019; 78/79: 32–46. https://doi.org/10.1016/j.matbio.2018.02.005
  21. Harris E., Cabral F. Ligand Binding and Signaling of HARE/Stabilin-2. Biomolecules. 2019; 9 (7): 273. https://doi.org/10.3390/biom9070273
  22. Marcotti S., Maki K., Reilly G.C., Lacroix D., Adachi T. Hyaluronic acid selective anchoring to the cytoskeleton: An atomic force microscopy study. PLoS One. 2018; 13 (10): e0206056. https://doi.org/10.1371/journal.pone.0206056
  23. Dhar D., Antonucci L., Nakagawa H., Kim J., Glitzner E., Caruso S., Karin M. Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling. Cancer Cell. 2018; 33 (6): 1061–77. https://doi.org/10.1016/j.ccell.2018.05.003
  24. Murai T. Lipid Raft-Mediated Regulation of Hyaluronan-CD44 Interactions in Inflammation and Cancer. Front Immunol. 2015; 6: 420. https://doi.org/10.3389/fimmu.2015.00420
  25. Janiszewska M., De Vito C., Le Bitoux M., Fusco C., Stamenkovic I. Transportin regulates nuclear import of CD44. J. Biol. Chem. 2010; 285 (40): 30548–57. https://doi.org/10.1074/jbc.M109.075838
  26. Arasu U., Kärnä R., Härkönen K., Oikari S., Koistinen A., Kröger H., Qu C., Lammi M., Rilla K. Human mesenchymal stem cells secrete hyaluronan-coated extracellular vesicles. Matrix Biol. 2017; 64: 54–8. https://doi.org/10.1016/j.matbio.2017.05.001
  27. Pandey M., Baggenstoss B., Washburn J., Harris E., Weigel P. The hyaluronan receptor for endocytosis (HARE) activates NF-κB-mediated gene expression in response to 40-400-kDa, but not smaller or larger, hyaluronans. J. Biol. Chem. 2013; 288 (20): 14068–79. https://doi.org/10.1074/jbc.M112.442889
  28. Morgan D. The cell cycle: principles of control. Yale J. Biol. Med. 2007; 80 (3): 141–42.
  29. Morrish F., Isern N., Sadilek M., Jeffrey M., Hockenbery D. c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry. Oncogene. 2009; 28 (27): 2485–91. https://doi.org/10.1038/onc.2009.112
  30. Pandey N., Vinod P.K. Mathematical modelling of reversible transition between quiescence and proliferation. PLoS One. 2018; 13 (6): e0198420. https://doi.org/10.1371/journal.pone.0198420
  31. Zwang Y., Sas-Chen A., Drier Y., Shay T., Avraham R., Lauriola M., Shema E., Lidor-Nili E., Jacob-Hirsch J., Yarden Y. Two phases of mitogenic signaling unveil roles for p53 and EGR1 in elimination of inconsistent growth signals. Mol Cell. 2011; 42: 524–35. https://doi.org/10.1016/j.molcel.2011.04.017
  32. Xu N., Lao Y., Zhang Y., Gillespie D.A. Akt: a double-edged sword in cell proliferation and genome stability. J. Oncol. 2012; 2012: 951724.
  33. Lee H., Jeong A., Ye S. Highlighted STAT3 as a potential drug target for cancer therapy. BMB Rep. 2019; 52 (7): 415–23. https://doi.org/10.5483/BMBRep.2019.52.7.152
  34. Bahrami S., Drabløs F. Gene regulation in the immediate-early response process. Adv Biol Regul. 2016; 62: 37–49.
  35. Blanchet E., Annicotte J., Lagarrigue S., Aguilar V., Clapé C., Chavey C., Fritz V., Casas F., Apparailly F., Auwerx J., Fajas L. E2F transcription factor-1 regulates oxidative metabolism. Nat Cell Biol. 2011; 13 (9): 1146–52. https://doi.org/10.1038/ncb2309
  36. Godar S., Weinberg R. Filling the mosaic of p53 actions: p53 represses RHAMM expression. Cell Cycle. 2008; 7 (22): 3479. https://doi.org/10.4161/cc.7.22.7320
  37. Inoue K., Fry E. Tumor suppression by the EGR1, DMP1, ARF, p53, and PTEN network. Cancer Invest. 2018; 36 (99–10): 520–36. https://doi.org/10.1080/07357907.2018.1533965
  38. Heldin P., Basu K., Kozlova I., Porsch H. HAS2 and CD44 in breast tumorigenesis. Adv Cancer Res. 2014; 123: 211–29. https://doi.org/10.1016/B978-0-12-800092-2.00008-3
  39. Liu M., Tolg C., Turley E. Dissecting the Dual Nature of Hyaluronan in the Tumor Microenvironment. Front Immunol. 2019; 10: 947. https://doi.org/10.3389/fimmu.2019.00947
  40. Mowbray C., Shams S., Chung G., Stanton A., Aldridge P., Suchenko A., Pickard R., Ali A., Hall J. High molecular weight hyaluronic acid: a two-pronged protectant against infection of the urogenital tract? Clin Transl Immunology. 2018; 7 (6): e1021. https://doi.org/10.1002/cti2.1021
  41. Zhu R., Huang Y., Tao Y., Wang S., Sun C., Piao H., Wang X. Hyaluronan up-regulates growth and invasion of trophoblasts in an autocrine manner via PI3K/AKT and MAPK/ERK1/2 pathways in early human pregnancy. Placenta. 2013; 34 (9): 784–91. https://doi.org/10.1016/j.placenta.2013.05.009
  42. Kothapalli D., Flowers J., Assoian R. Differential activation of ERK and Rac mediates the pro-liferative and anti-proliferative effects of hyaluronan and CD44. J. Biol. Chem. 2008; 283 (46): 31823–9 https://doi.org/10.1074/jbc.M802934200
  43. Evanko S., Potter-Perigo S., Petty L., Workman G., Wight T. Hyaluronan Controls the Deposition of Fibronectin and Collagen and Modulates TGF-β1 Induction of Lung Myofibroblasts. Matrix Biol. 2015; 42: 74–92. https://doi.org/10.1016/j.matbio.2014.12.001
  44. Puré E., Assoian R. Rheostatic signaling by CD44 and hyaluronan. Cell Signal. 2009; 21 (5): 651–5. https://doi.org/10.1016/j.cellsig.2009.01.024
  45. Cyphert J., Trempus C., Garantziotis S. Size Matters: Molecular Weight Specificity of Hyaluronan Effects in Cell Biology. Int J. Cell. Biol. 2015; 2015: 563818.
  46. Heldin P., Lin C., Kolliopoulos C., Chen Y., Skandalis S. Regulation of hyaluronan biosynthesis and clinical impact of excessive hyaluronan production. Matrix Biol. 2019; 78–79: 100–17. https://doi.org/10.1016/j.matbio.2018.01.017
  47. Rayahin J., Buhrman J., Zhang Y., Gemeinhart R. High and low molecular weight hyaluronic acid differentially influence macrophage activation. ACS Biomater Sci Eng. 2015; 1 (7): 481–93. https://doi.org/10.1021/acsbiomaterials.5b00181
  48. Albano G., Bonanno A., Cavalieri L., Ingrassia E., Di Sano C., Siena L., Riccobono L., Gagliardo R., Profita M. Effect of High, Medium, and Low Molecular Weight Hyaluronan on Inflammation and Oxidative Stress in an In Vitro Model of Human Nasal Epithelial Cells. Mediators Inflamm. 2016: 8727289. https://doi.org/10.1155/2016/8727289
  49. Meran S., Luo D., Simpson R., Martin J., Wells A., Steadman R., Phillips A. Hyaluronan facilitates transforming growth factor-β1-dependent proliferation via CD44 and epidermal growth factor receptor interaction. J. Biol. Chem. 2011; 286: 17618–30. https://doi.org/10.1074/jbc.M111.226563
  50. Kuo Y., Fang W., Huang C., Tsai S., Wang Y., Yang C., Wu L. Hyaluronan synthase 3 mediated oncogenic action through forming inter-regulation loop with tumor necrosis factor alpha in oral cancer. Oncotarget. 2017; 8: 15563–83. https://doi.org/10.18632/oncotarget.14697
  51. Gao F., Yang C., Mo W., Liu Y., He Y. Hyaluronan oligosaccharides are potential stimulators to angiogenesis via RHAMM mediated signal pathway in wound healing. Clin Invest Med. 2008; 31 (3): 106–16. https://doi.org/10.25011/cim.v31i3.3467
  52. Bauer J., Rothley M., Schmaus A., Quagliata L., Ehret M., Biskup M., Orian-Rousseau V. TGFβ counteracts LYVE-1-mediated induction of lymphangiogenesis by small hyaluronan oligosaccharides. J. Mol. Med. (Berl). 2018; 96 (2): 199–209.
  53. Kim Y., Lee Y., Choe J., Lee H., Kim Y., Jeoung D. CD44-EGFR interaction mediates hyaluronic acid-promoted cell motility by activating protein kinase C signaling involving Akt, Rac1, Phox, reactive oxygen species, focal adhesion kinase, and MMP-2. J. Biol. Chem. 2008; 283 (33): 22513–28.
  54. Schmitz I., Ariyoshi W., Takahashi N., Knudson W. Hyaluronan oligosaccharide treatment of chondrocytes stimulates expression of both HAS-2 and MMP-3, but by different signaling pathways. Osteoarthritis Cartilage. 2010; 18: 447–54. https://doi.org/10.1016/j.joca.2009.10.007
  55. Nam K., Oh S., Lee K., Yoo S., Shin I. CD44 regulates cell proliferation, migration, and invasion via modulation of c-Src transcription in human breast cancer cells. Cell Signal. 2015; 27 (9): 1882–94. https://doi.org/10.1016/j.cellsig.2015.05.002
  56. Avenoso A., Bruschetta G., D’Ascola A., Scuruchi M., Mandraffino G., Gullace R., Saitta A., Campo S. Hyaluronan fragments produced during tissue injury: A signal amplifying the inflammatory response. Arch Biochem Biophys. 2019; 663: 228–38. https://doi.org/10.1016/j.abb.2019.01.015
  57. Khurana S., Riehl T., Moore B., Fassan M., Rugge M., Romero-Gallo J., Noto J., Peek R.Jr., Stenson W., Mills J. The hyaluronic acid receptor CD44 coordinates normal and metaplastic gastric epithelial progenitor cell proliferation. J. Biol. Chem. 2013; 288 (22): 16085–97. https://doi.org/10.1074/jbc.M112.445551
  58. Nishida-Fukuda H., Araki R., Shudou M., Okazaki H., Tomono Y., Nakayama H., Fukuda S., Sakaue T., Shirakata Y., Sayama K., Hashimoto K., Detmar M., Higashiyama S., Hirakawa S. Ectodomain Shedding of Lymphatic Vessel Endothelial Hyaluronan Receptor 1 (LYVE-1) Is Induced by Vascular Endothelial Growth Factor A (VEGF-A). J. Biol. Chem. 2016; 291 (20): 10490–500. https://doi.org/10.1074/jbc.M115.683201
  59. Lichtenthaler S., Lemberg M.K., Fluhrer R. Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments. EMBO J. 2018; 37 (15): e99456. https://doi.org/10.15252/embj.201899456
  60. Carpenter G., Pozzi A. Cell responses to growth factors: the role of receptor tyrosine kinase intracellular domain fragments. Sci Signal. 2012; 5 (243): 42. https://doi.org/10.1126/scisignal.2003526
  61. Merilahti J., Elenius K. Gamma-secretase-dependent signaling of receptor tyrosine kinases. Oncogene. 2019; 38 (2): 151–63. https://doi.org/10.1038/s41388-018-0465-z
  62. Miletti-González K., Murphy K., Kumaran M., Ravindranath A., Wernyj R. Identification of function for CD44 intracytoplasmic domain (CD44-ICD): modulation of matrix metalloproteinase 9 (MMP-9) transcription via novel promoter response element. J. Biol. Chem. 2012; 287 (23): 18995–9007. https://doi.org/10.1074/jbc.M111.318774
  63. Su M., Wang P., Wang X., Zhang M., Wei S., Liu K., Han S., Han X., Deng Y., Shen L. Nuclear CD44 Mediated by Importin β Participated in Naive Genes Transcriptional Regulation in C3A-iCSCs. Int J. Biol. Sci. 2019; 15 (6): 1252–60. https://doi.org/10.7150/ijbs.28235
  64. Park D., Kim Y., Kim H., Kim K., Lee Y., Choe J., Hahn J., Lee H., Jeon J., Choi C., Kim Y., Jeoung D. Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGFβ receptor interaction via CD44-PKCδ. Mol Cells. 2012; 33 (6): 563–74. https://doi.org/10.1007/s10059-012-2294-1
  65. Grass G., Tolliver L., Bratoeva M., Toole B. CD147, CD44, and the epidermal growth factor receptor (EGFR) signaling pathway cooperate to regulate breast epithelial cell invasiveness. J. Biol. Chem. 2013; 288 (36): 26089–104. https://doi.org/10.1074/jbc.M113.497685
  66. Nikitovic D., Kouvidi K., Karamanos N., Tzanakakis G. The roles of hyaluronan/RHAMM/CD44 and their respective interactions along the insidious pathways of fibrosarcoma progression. Biomed Res Int. 2013; 2013: 929531. https://doi.org/10.1155/2013/929531
  67. Yoo B., Gredler R., Chen D., Santhekadur P., Fisher P., Sarkar D. С-Met activation through a novel pathway involving osteopontin mediates oncogenesis by the transcription factor LSF. J. Hepatol. 2011; 55 (6): 1317–24. https://doi.org/10.1016/j.jhep.2011.02.036
  68. Chu Q., Huang H., Huang T., Cao L., Peng L., Shi S., Zheng L., Xu L., Zhang S., Huang J., Li X., Qian C., Huang B. Extracellular serglycin upregulates the CD44 receptor in an autocrine manner to maintain self-renewal in nasopharyngeal carcinoma cells by reciprocally activating the MAPK/β-catenin axis. Cell Death Dis. 2016; 7: e2456. https://doi.org/10.1038/cddis.2016.287