Bone and soft tissue sarcomas, tumors of the skinBone and soft tissue sarcomas, tumors of the skinСаркомы костей, мягких тканей и опухоли кожи2219-46142782-3687Publishing House ABV Press498SOFT TISSUE SARCOMASСАРКОМЫ МЯГКИХ ТКАНЕЙCRABP1 and CRABP2 expression in soft tissue sarcomasЭкспрессия CRABP1 и CRABP2 в саркомах мягких тканейTchevkinaE. M.ЧевкинаЕ. М.
Russian Federation
tchevkina@mail.ruFavorskayaI. A.ФаворскаяИ. А.
Russian Federation
KainovY. A.КаиновЯ. А.
Russian Federation
ChemerisG. Y.ЧемерисГ. Ю.
Russian Federation
KomelkovA. V.КомельковА. В.
Russian Federation
DyakovaN. A.ДьяковаН. А.
Russian Federation
FGBU N.N. Blokhin Russian Cancer Research CenterФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» РАМН0302201351475303022022Copyright ©; 2013, Tchevkina E.M., Favorskaya I.A., Kainov Y.A., Chemeris G.Y., Komelkov A.V., Dyakova N.A.Copyright ©; 2013, Чевкина Е.М., Фаворская И.А., Каинов Я.А., Чемерис Г.Ю., Комельков А.В., Дьякова Н.А.2013Tchevkina E.M., Favorskaya I.A., Kainov Y.A., Chemeris G.Y., Komelkov A.V., Dyakova N.A.Чевкина Е.М., Фаворская И.А., Каинов Я.А., Чемерис Г.Ю., Комельков А.В., Дьякова Н.А.https://creativecommons.org/licenses/by/4.0https://sarbon.abvpress.ru/jour/article/view/498

Background. The study is devoted to the research of CRABP1 and CRABP2 mRNA as well as CRABP1 protein expression in human soft tissue sarcomas. Methods. Real time PCR, IHC analysis. Results. Here we for the first time studied the CRABP1 and CRABP2 genes expression by real time PCR in the samples of malignant mesenchymal tumors, including synovial sarcomas, malignant fibrous histiocytomas, malignant schwannomas and liposarcomas. We also analyzed CRABP1 protein level using immunohistochemistry in the samples of monophasic synovial sarcomas. Increase of CRABP1 and CRABP2 mRNA levels was revealed only in the synovial sarcomas and malignant fibrous histiocytomas samples (46% for CRABP1 and 54% for CRABP2). Opposite to synovial sarcomas and malignant fibrous histiocytomas, in the samples of malignant schwannomas and liposarcomas no elevation of CRABP1 or CRABP2 mRNA level was found; moreover, in 40% of these kind of tumors the decrease of CRABP1 mRNA level was observed. Immunohistochemical analysis revealed high level of CRABP1 protein in 100% of monophasic synovial sarcomas. Conclusion. The obtained results pointed on the differential CRABP1, -2 proteins expression in malignant soft tissue tumors depending on the histological type. The presented data open wide perspectives for further studies of CRABP1 as a potential prognostic marker and target for translational therapy of synovial sarcomas.

Цель работы. исследование экспрессии мРНК CRABP1 и CRABP2 и белка CRABP1 в саркомах мягких тканей человека. Материалы и методы. ПЦР в реальном времени, ИГХ анализ. Результаты. В работе впервые проведен анализ экспрессии мРНк генов CRABP1 и CRABP2 методом ПЦР в реальном времени в образцах злокачественных новообразований мягких тканей, включая синовиальные саркомы, злокачественные фиброзные гистиоцитомы, злокачественные шванномы и липосаркомы, а также иммуногистохимический анализ экспрессии белка CRABP1 в образцах монофазных синовиальных сарком. Повышение уровня мРНк как CRABP1, так и CRABP2 было выявлено исключительно в образцах синовиальных сарком и злокачественных фиброзных гистиоцитом (46% для CRABP1 и 54% для CRABP2). Б отличие от синовиальных сарком и злокачественных фиброзных гистиоцитом в липосаркомах и злокачественных шванномах не было отмечено повышения экспрессии ни CRABP1, ни CRABP2; более того, для 40% данных опухолей было характерно снижение количества мРНК CRABP1. По данным ИГХ, высокий уровень белка CRABP1 обнаруживается в 100% образцов монофазных синовиальных сарком. Заключение. Полученные результаты свидетельствуют о дифференциальном характере экспрессии белков CRABP в злокачественных опухолях мягких тканей в зависимости от гистологического типа. Полученные данные открывают перспективы для дальнейших исследований белка CRABP1 в качестве потенциального прогностического маркера и мишени для таргетной терапии синовиальных сарком.

синовиальные саркомызлокачественные фиброзные гистиоцитомылипосаркомызлокачественные шванномыCRABP1CRABP2игх анализпЦР в реальном времениsynovial sarcomasmalignant fibrous histiocytomasmalignant schwannomasliposarcomasCRABP1CRABP2IHC analysisreal-time PCRAhlquist T., Lind G.E., Costa V.L. et al. Gene methylation profiles of normal mucosa, and benign and malignant colorectal tumors identify early onset markers. Mol. Cancer. 2008, v. 7, p. 94.Banz C., Ungethuem U., Kuban R.J. et al. The molecular signature of endometriosis-associated endometrioid ovarian cancer differs significantly from endometriosis-independent endometrioid ovarian cancer. Fertil. Steril. 2010, v. 94, No. 4, p. 1212-1217.Blaese M.A., Santo-Hoeltje L., Rodemann H.P. CRABPI expression and the mediation of the sensitivity of human tumor cells to retinoic acid and irradiation. Int. J. Radiat. Biol. 2003, v. 79, No. 12, p. 981-991.Breitman T.R., Selonick S.E., Collins S.J. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc. Natl. Acad. Sci. USA. 1980, v. 77, No. 5, p. 2936-2940.Budhu A., Gillilan R., Noy N. Localization of the RAR interaction domain of cellular retinoic acid binding protein-II. J. Mol. Biol. 2001, v. 305, No. 4, p. 939-949.Bushue N., Wan Y.J. Retinoid pathway and cancer therapeutics. Adv. Drug Deliv. Rev. 2010, v. 62, No. 13, p. 1285-1298.Calmon M.F., Rodrigues R.V., Kaneto C.M. et al. Epigenetic silencing of CRABP2 and MX1 in head and neck tumors. Neoplasia. 2009, v. 11, No. 12, p. 1329-1339.Dressler D., Sarang Z., Szondy Z. et al. Expression of retinoid-related genes in serum-free cultures of normal, immortalized and malignant human oral keratinocytes. Int. J. Oncol. 2002, v. 20, No. 5, p. 897-903.Eichele G. Retinoic acid induces a pattern of digits in anterior half wing buds that lack the zone of polarizing activity. Development. 1989, v. 107, No. 4, p. 863-867.Guruvayoorappan C., Kuttan G. 13 cis-retinoic acid regulates cytokine production and inhibits angiogenesis by disrupting endothelial cell migration and tube formation. J. Exp. Ther. Oncol. 2008, v. 7, No. 3, p. 173-182.Hawthorn L., Stein L., Varma R. et al. TIMP1 and SERPIN-A overexpression and TFF3 and CRABP1 underexpression as biomarkers for papillary thyroid carcinoma. Head Neck. 2004, v. 26, No. 12, p.1069-1083.Hoffmann S., Rockenstein A., Ramaswamy A. et al. Retinoic acid inhibits angiogenesis and tumor growth of thyroid cancer cells. Mol. Cell. Endocrinol. 2007, v. 264, No. 1-2, p. 74-81.Itoh Y., Ishikawa M., Naito M., Hashimoto Y. Protein knockdown using methyl bestatin-ligand hybrid molecules: design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins. J. Am Chem. Soc. 2010, v. 132, No. 16, p. 5820-5826.Lee H.S., Kim B.H., Cho N.Y. et al. Prognostic implications of and relationship between CpG island hypermethylation and repetitive DNA hypomethylation in hepatocellular carcinoma. Clin. Cancer Res. 2009, v. 15, No. 3, p. 812-820.Lee J.H., Yoon J.H., Yu S.J. et al. Retinoic acid and its binding protein modulate apoptotic signals in hypoxic hepatocellular carcinoma cells. Cancer Lett. 2010, v. 295, No. 2, p. 229-235.Levadoux-Martin M., Li Y., Blackburn A. et al. Perinuclear localisation of cellular retinoic acid binding protein I mRNA. Biochem. Biophys. Res. Commun. 2006, v. 340, No. 1, p. 326-331.Lu Y., Lemon W., Liu P.Y. et al. A gene expression signature predicts survival of patients with stage I non-small cell lung cancer. PLoS Med. 2006, v. 3, No. 12, p. e467.Luo P., Lin M., Lin M. et al. Function of retinoid acid receptor alpha and p21 in all-trans-retinoic acid-induced acute T-lymphoblastic leukemia apoptosis. Leuk. Lymphoma. 2009, v. 50, No. 7, p.1183-1189.Mallikarjuna K., Sundaram C.S., Sharma Y. et al. Comparative proteomic analysis of differentially expressed proteins in primary retinoblastoma tumors. Proteomics Clin. Appl. 2010, v. 4, No. 4, p. 449-463.Miyake T., Ueda Y., Matsuzaki S. et al. CRABP1-reduced expression is associated with poorer prognosis in serous and clear cell ovarian adenocarcinoma. J. Cancer Res. Clin. Oncol. 2011, v. 137, No. 4, p. 715-722.Nagayama S., Katagiri T., Tsunoda T. et al. Genome-wide analysis of gene expression in synovial sarcomas using a cDNA microarray. Cancer Res. 2002, v. 62, No. 20, p. 5859-5866.Neubauer H., Clare S.E., Kurek R. et al. Breast cancer proteomics by laser capture microdissection, sample pooling, 54-cm IPG IEF, and differential iodine radioisotope detection. Electrophoresis. 2006, v. 27, No. 9, p. 1840-1852.Okuducu A.F., Janzen V., Ko Y. et al. Cellular retinoic acid-binding protein 2 is down-regulated in prostate cancer. Int. J. Oncol. 2005, v. 27, No. 5, p. 1273-1282.Pavone M.E., Reierstad S. Sun H. et al. Altered retinoid uptake and action contributes to cell survival in endometriosis. J. Clin. Endocrinol. Metab. 2010, v. 95, No. 11, p. E300-9.Pfoertner S., Goelden U., Hansen W. et al. Cellular retinoic acid binding protein I: expression and functional influence in renal cell carcinoma. Tumour Biol. 2005, v. 26, No. 6, p. 313-323.Ross A.C. Cellular metabolism and activation of retinoids: roles of cellular retinoid-binding proteins. FASEB J. 1993, v. 7, No. 2, p. 317-327.Ruff S.J., Ong D.E. Cellular retinoic acid binding protein is associated with mitochondria. FEBS Lett. 2000, v. 487, No. 2, p. 282-286.Sadikoglou E., Magoulas G., Theodoropoulou C. et al. Effect of conjugates of all-trans-retinoic acid and shorter polyene chain analogues with amino acids on prostate cancer cell growth. Eur. J. Med. Chem. 2009, v. 44, No. 8, p. 3175-3187.Siddiqui N.A., Thomas E.J., Dunlop W., Redfern C.P. Retinoic acid receptors and retinoid binding proteins in endometrial adenocarcinoma: differential expression of cellular retinoid binding proteins in endometrioid tumors. Int. J. Cancer. 1995, v. 64, No. 4, p. 253-263.Tanaka K., Imoto I., Inoue J. et al. Frequent methylation-associated silencing of a candidate tumor-suppressor, CRABP1, in esophageal squamous-cell carcinoma. Oncogene. 2007, v. 26, No. 44, p. 6456-6468.Tang X.H., Vivero M., Gudas L.J. Overexpression of CRABPI in suprabasal keratinocytes enhances the proliferation of epidermal basal keratinocytes in mouse skin topically treated with all-trans retinoic acid. Exp. Cell. Res. 2008, v. 314, No. 1, p. 38-51.Won J.Y., Nam E.C., Yoo S.J. et al. The effect of cellular retinoic acid binding protein-I expression on the CYP26-mediated catabolism of all-trans retinoic acid and cell proliferation in head and neck squamous cell carcinoma. Metabolism. 2004, v. 53, No. 8, p. 1007-1012.Wu X., Blanck A., Norstedt G. et al. Identification of genes with higher expression in human uterine leiomyomas than in the corresponding myometrium. Mol. Hum. Reprod. 2002, v. 8, No. 3, p. 246-254.Каинов Я.А., Фаворская И.А., Антошина Е.Е. и соавт. Роль белка CRABP1 в формировании высокометастазного фенотипа RSV-трансформированных фибробластов сирийского хомяка. Российский Биотерапевтический Журнал. 2011, v. 10, No. 2, p. 37-44.