ХИТИНАЗОПОДОБНЫЕ БЕЛКИ КАК ПЕРСПЕКТИВНЫЕ МАРКЕРЫ ПРИ ЗЛОКАЧЕСТВЕННЫХ НОВООБРАЗОВАНИЯХ

В обзоре проанализированы данные о роли хитиназоподобных белков (CLP), принадлежащих к семейству  белков, содержащих Glyco_18 домен и не обладающих ферментативной активностью, при различных  злокачественных новообразованиях. У человека идентифицировано 3 таких белка: YKL-40 (CHI3L1), YKL-39  (CHI3L2) и стабилин-связывающий CLP (SI-CLP). Хитиназоподобные белки, продуцируемые различными типами  клеток, в том числе опухолевыми, проявляют активность как цитокины и ростовые факторы, а также  они вовлечены в процессы воспаления. Высокий уровень CLP определяется в циркулирующей крови при  воспалительных заболеваниях и разных локализациях злокачественных опухолей. Освещены данные о  ключевых функциях CLP в физиологических и патологических условиях. Проанализированы сведения о  вовлечении CLP в процессы инвазии, метастазирования, ангиогенеза, их связи с опухолевой прогрессией.  Представлены собственные результаты, подтверждающие перспективность разработки прогностических и  предсказательных маркеров на основе CLP при злокачественных новообразованиях.

1. Kzhyshkowska J., Gratchev, A., Goerdt, S. Human chitinases and chitinase-like proteins as indicators for inflammation and cancer. Biomark Insights. 2007 May 3; 2: 128–46.

2. Shuhui L., Mok Y.K., Wong W.S. Role of mammalian chitinases in asthma. Int Arch Allergy Immunol. 2009; 149(4): 369–77. doi: 10.1159/000205583.

3. Donnelly L.E., Barnes, P.J. Acidic mammalian chitinase–a potential target for asthma therapy. Trends Pharmacol Sci. 2004 Oct; 25(10): 509–11. doi: 10.1016/j.tips.2004.08.002.

4. Zhu Z., Zheng T., Homer R.J., Kim Y.-K., Chen N.Y., Cohn L., Hamid Q., Elias J.A. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science. 2004 Jun 11; 304(5677): 1678–82. doi: 10.1126/science.1095336.

5. Boot R.G., Renkema G.H., Strijland A., van Zonneveld A.J., Aerts J.M. Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages. J Biol Chem. 1995 Nov 3; 270(44): 26252–6.

6. Boven L.A., van Meurs M., Boot R.G., Mehta A., Boon L., Aerts J.M., Laman J.D. Gaucher cells demonstrate a distinct macrophage phenotype and resemble alternatively activated macrophages. Am J Clin Pathol. 2004 Sep; 122(3): 359–69. doi: 10.1309/BG5V-A8JR-DQH1-M7HN.

7. Hu B., Trinh K., Figueira W.F., Price P.A. Isolation and sequence of a novel human chondrocyte protein related to mammalian members of the chitinase protein family. J Biol Chem. 1996 Aug 9; 271(32): 19415–20.

8. Jin H.M., Copeland N.G., Gilbert D.J., Jenkins N.A., Kirkpatrick R.B., Rosenberg M. Genetic characterization of the murine Ym1 gene and identification of a cluster of highly homologous genes. Genomics. 1998 Dec 1; 54(2): 316–22. doi: 10.1006/geno.1998.5593.

9. Kzhyshkowska J., Mamidi S., Gratchev A., Kremmer E., Schmuttermaier C., Krusell L., Haus G., Utikal J., Schledzewski K., Scholtze J., Goerdt S. Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood. 2006 Apr 15; 107(8): 3221– 8. doi: 10.1182/blood-2005-07-2843.

10. Kzhyshkowska J., Yin S., Liu T., Riabov V., Mitrofanova I. Role of chitinase-like proteins in cancer. Biol Chem. 2016 Mar; 397(3): 231–47. doi: 10.1515/hsz-2015-0269. doi: 10.1515/hsz-2015-0269.

11. Ranok A., Wongsantichon J., Robinson R.C., Suginta W. Structural and thermodynamic insights into chitooligosaccharide binding to human cartilage chitinase 3-like protein 2 (CHI3L2 or YKL-39). J Biol Chem. 2015 Jan 30; 290(5): 2617–29. doi: 10.1074/jbc.M114.588905.

12. Schimpl M., Rush C.L., Betou M., Eggleston I.M., Recklies A.D., van Aalten D.M. Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties. Biochem J. 2012 Aug 15; 446(1): 149–57. doi: 10.1042/BJ20120377.

13. Bigg H.F., Wait R., Rowan A.D., Cawston T.E. The mammalian chitinase-like lectin, YKL-40, binds specifically to type I collagen and modulates the rate of type I collagen fibril formation. J Biol Chem. 2006 Jul 28; 281(30): 21082–95. doi: 10.1074/jbc.M601153200.

14. Fusetti F., Pijning T., Kalk K.H., Bos E., Dijkstra B.W. Crystal structure and carbohydrate-binding properties of the human cartilage glycoprotein-39. J Biol Chem. 2003 Sep 26; 278(39): 37753‑60. doi: 10.1074/jbc.M303137200.

15. Renkema G.H., Boot R.G., Au F.L., Donker-Koopman W.E., Strijland A., Muijsers A.O., Hrebicek M., Aerts J.M. Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages. Eur J Biochem. 1998 Jan 15; 251(1‑2): 504–9.

16. Nishikawa K.C., Millis A.J. gp38k (CHI3L1) is a novel adhesion and migration factor for vascular cells. Exp Cell Res. 2003 Jul 1; 287(1): 79–87.

17. Meng G., Zhao Y., Bai X., Liu Y., Green T.J., Luo M., Zheng X. Structure of human stabilin-1 interacting chitinase-like protein (SI-CLP) reveals a saccharide-binding cleft with lower sugar-binding selectivity. J Biol Chem. 2010 Dec 17; 285(51): 39898–904. doi: 10.1074/jbc.M110.130781.

18. Chang N.C., Hung S.I., Hwa K.Y., Kato I., Chen J.E., Liu C.H., Chang A.C. A macrophage protein, Ym1, transiently expressed during inflammation is a novel mammalian lectin. J Biol Chem. 2001 May 18; 276(20): 17497–506. doi: 10.1074/jbc.M010417200.

19. Sekine T., Masuko-Hongo K., Matsui T., Asahara H., Takigawa M., Nishioka K., Kato T. Recognition of YKL-39, a human cartilage related protein, as a target antigen in patients with rheumatoid arthritis. Ann Rheum Dis. 2001 Jan; 60(1): 49–54.

20. Shao R. Secreted glycoprotein YKL-40: A potential cancer biomarker and therapeutic target. Integr Cancer Sci Therap. 2018; 5(1): 1–1. doi: 10.15761/ICST.1000268.

21. Johansen J.S. Studies on serum YKL-40 as a biomarker in diseases with inflammation, tissue remodelling, fibroses and cancer. Dan Med Bull. 2006 May; 53(2): 172–209.

22. Rathcke C.N., Vestergaard H. YKL-40, a new inflammatory marker with relation to insulin resistance and with a role in endothelial dysfunction and atherosclerosis. Inflamm Res. 2006 Jun; 55(6): 221‑7. doi: 10.1007/s00011-006-0076-y.

23. Johansen J.S., Jensen B.V., Roslind A., Nielsen D., Price P.A. Serum YKL-40, a new prognostic biomarker in cancer patients? Cancer Epidemiol Biomarkers Prev. 2006 Feb; 15(2): 194–202. doi: 10.1158/1055-9965.EPI-05-0011.

24. Suzuki T., Hashimoto S., Toyoda N., Nagai S., Yamazaki N., Dong H.Y., Sakai J., Yamashita T., Nukiwa T., Matsushima K. Comprehensive gene expression profile of LPS-stimulated human monocytes by SAGE. Blood 2000; 96: 2584–91.

25. Liu T., Larionova I., Litviakov N., Riabov V., Zavyalova M., Tsyganov M., Buldakov M., Song B., Moganti K., Kazantseva P., Slonimskaya E., Kremmer E., Flatley A., Klüter H., Cherdyntseva N., Kzhyshkowska J. Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy. Oncoimmunology. 2018 Mar 13; 7(6): e1436922. doi: 10.1080/2162402X.2018.1436922

26. Shao R., Hamel K., Petersen L., Cao Q.J., Arenas R.B., Bigelow C., Bentley B., Yan W. YKL-40, a secreted glycoprotein, promotes tumor angiogenesis. Oncogene. 2009 Dec 17; 28(50): 4456–68. doi: 10.1038/onc.2009.292.

27. Francescone R.A., Scully S., Faibish M., Taylor S.L., Oh D., Moral L., Yan W., Bentley B., Shao R. Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma. J Biol Chem. 2011 Apr 29; 286(17): 15332–43. doi: 10.1074/jbc.M110.212514.

28. Faibish M., Francescone R., Bentley B., Yan W., Shao R. A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers. Mol Cancer Ther. 2011; 10: 742–51. doi: 10.1158/1535-7163.MCT-10-0868.

29. Salamon J., Hoffmann T., Elies E., Peldschus K., Johansen J.S., Lüers G., Schumacher U., Wicklein D. Antibody directed against human YKL-40 increases tumor volume in a human melanoma xenograft model in scid mice. PLoS One. 2014 Apr 21; 9(4): e95822. doi: 10.1371/journal.pone.0095822.

30. Wan G., Xiang L., Sun X., Wang X., Li H., Ge W., Cao F. Elevated YKL-40 expression is associated with a poor prognosis in breast cancer patients. Oncotarget. 2017 Jan 17; 8(3): 5382–5391. doi: 10.18632/oncotarget.14280.

31. Saidi A., Javerzat S., Bellahcène A., De Vos J., Bello L., Castronovo V., Deprez M., Loiseau H., Bikfalvi A., Hagedorn M. Experimental antiangiogenesis causes upregulation of genes associated with poor survival in glioblastoma. Int J Cancer. 2008 May 15; 122(10): 2187‑98. doi: 10.1002/ijc.23313.

32. Nio J., Fujimoto W., Konno A., Kon Y., Owhashi M., Iwanaga T. Cellular expression of murine Ym1 and Ym2, chitinase family proteins, as revealed by in situ hybridization and immunohistochemistry. Histochem Cell Biol. 2004 Jun; 121(6): 473–82. doi: 10.1007/s00418-004-0654-4.

33. Kawada M., Seno H., Kanda K., Nakanishi Y., Akitake R., Komekado H., Kawada K., Sakai Y., Mizoguchi E., Chiba T. Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer. Oncogene. 2012 Jun 28; 31(26): 3111–23. doi: 10.1038/onc.2011.498.

34. Tang H., Sun Y., Shi Z., Huang H., Fang Z., Chen J., Xiu Q., Li B. YKL-40 induces IL-8 expression from bronchial epithelium via MAPK (JNK and ERK) and NF-κB pathways, causing bronchial smooth muscle proliferation and migration. J Immunol. 2013 Jan 1; 190(1): 438–46. doi: 10.4049/jimmunol.1201827.

35. Jefri M., Huang Y.N., Huang W.C., Tai C.S., Chen W.L. YKL-40 regulated epithelial- mesenchymal transition and migration/invasion enhancement in non-small cell lung cancer. BMC Cancer. 2015 Aug 15; 15: 590. doi: 10.1186/s12885-015-1592-3.

36. Schultz N.A., Johansen J.S. YKL-40-A Protein in the Field of Translational Medicine: A Role as a Biomarker in Cancer Patients? Cancers (Basel). 2010 Jul 12; 2(3): 1453‑91. doi: 10.3390/cancers2031453.

37. Shao R., Cao Q.J., Arenas R.B., Bigelow C., Bentley B., Yan W. Breast cancer expression of YKL-40 correlates with tumour grade, poor differentiation, and other cancer markers. Br J Cancer. 2011 Oct 11; 105(8): 1203–9. doi: 10.1038/bjc.2011.347.

38. Litviakov N., Tsyganov M., Larionova I., Ibragimova M., Deryusheva I., Kazantseva P., Slonimskaya E., Frolova I., Choinzonov E., Cherdyntseva N., Kzhyshkowska J. Expression of M2 macrophage markers YKL-39 and CCL18 in breast cancer is associated with the effect of neoadjuvant chemotherapy. Cancer Chemother Pharmacol. 2018 Jul; 82(1): 99–109. doi: 10.1007/s00280-018-3594-8.

39. Kavsan V.M., Baklaushev V.P., Balynska O.V., Iershov A.V., Areshkov P.O., Yusubalieva G.M., Grinenko N.P., Victorov I.V., Rymar V.I., Sanson M., Chekhonin V.P. Gene Encoding Chitinase 3-Like 1 Protein (CHI3L1) is a Putative Oncogene. Int J Biomed Sci. 2011 Sep; 7(3): 230–7.

40. Itik V., Kemik O., Kemik A., Dulger A.C., Sümer A., Soyoral Y.U., Begenik H., Purisa S., Kotan C. Serum YKL-40 Levels in Patients with Gastric Cancer. Biomark Cancer. 2011 May 4; 3: 25–30. doi: 10.4137/BIC.S7154.

41. Dupont J., Tanwar M.K., Thaler H.T., Fleisher M., Kauff N., Hensley M.L., Sabbatini P., Anderson S., Aghajanian C., Holland E.C., Spriggs D.R. Early detection and prognosis of ovarian cancer using serum YKL-40. J Clin Oncol 2004; 22: 3330–9. doi: 10.1200/JCO.2004.09.112.

42. Yasar O., Akcay T., Obek C., Turegun F.A. Diagnostic potential of YKL-40 in bladder cancer. Urol Oncol. 2016 Jun; 34(6): 257.e19‑24. doi: 10.1016/j.urolonc.2016.02.003.

43. Bi J., Lau S.H., Lv Z.L., Xie D., Li W., Lai Y.R., Zhong J.M., Wu H.Q., Su Q., He Y.L., Zhan W.H., Wen J.M., Guan X.Y. Overexpression of YKL-40 is an independent prognostic marker in gastric cancer. Hum Pathol. 2009 Dec; 40(12): 1790–7. doi: 10.1016/j.humpath.2009.07.005.

44. Johansen J.S., Drivsholm L., Price P.A., Christensen I.J. High serum YKL-40 level in patients with small cell lung cancer is related to early death. Lung Cancer. 2004; 46: 333–340. doi: 10.1016/j.lungcan.2004.05.010.

45. Cintin C., Johansen J.S., Christensen I.J., Price P.A., Sørensen S., Nielsen H.J. High serum YKL-40 level after surgery for colorectal carcinoma is related to short survival. Cancer. 2002; 95: 267–274. doi: 10.1002/cncr.10644.

46. Johansen J.S., Bojesen S.E., Mylin A.K., Frikke-Schmidt R., Price P.A., Nordestgaard B.G. Elevated plasma YKL-40 predicts increased risk of gastrointestinal cancer and decreased survival after any cancer diagnosis in the general population. J Clin Oncol. 2009 Feb 1; 27(4): 572–8. doi: 10.1200/JCO.2008.18.8367.

47. Chang S.T., Zahn J.M., Horecka J., Kunz P.L., Ford J.M., Fisher G.A., Le Q.T., Chang D.T., Ji H., Koong A.C. Identification of a biomarker panel using a multiplex proximity ligation assay improves accuracy of pancreatic cancer diagnosis. J Transl Med. 2009 Dec 11; 7: 105. doi: 10.1186/1479-5876-7-105.