Abstract
Introduction. Endometrial cancer is the leading oncogynecological pathology in Russia. Proteasomes, multisubunit proteolytic complexes, play an important role in the development of endometrial cancer.
Aim. Evaluation of the prognostic significance of proteasome activity and the level of immune subunits of proteasomes LMP2 and LMP7 in relation to overall and disease-free survival in endometrial cancer.
Materials and methods. The study included 90 patients with endometrial cancer, stage I-III. Chymotrypsin-like activity of proteasomes was determined in clarified homogenates of tumor and intact endometrial tissue by hydrolysis of the fluorogenic oligopeptide Suc-LLVY-AMC (Sigma). The content of LMP2 and LMP7 immune subunits of the proteasomes was determined by Western blotting. Results. Аn increase in the chymotrypsin-like activity of proteasomes in the tumor tissue was revealed compared to the unchanged endometrium, as well as in stage III tumors compared to stages I and II. In the endometrial cancer tissue, an increase in the content of LMP2 and LMP7 subunits was observed in relation to the unchanged tissue. One-way analysis of proteasome parameters showed that chymotrypsin-like activity of proteasomes is associated with 3-year relapse-free survival of patients with endometrial cancer, and the content of the proteasome LMP2 subunit is associated with overall survival.
Conclusion. The chymotrypsin-like activity of proteasomes and the content of the LMP2 subunits in the tumor tissue can be considered as additional criteria for recurrence and overall survival, which in turn will allow planning an adequate amount of treatment for patients.
References
Злокачественные новообразования в России в 2020 году (заболеваемость и смертность). Под ред. Каприна А.Д, Старинского В.В., Шахзадовой А.О. М.: МНИОИ им. П.А. Герцена − филиал ФГБУ «НМИЦ радиологии» Минздрава России. 2021:252 [Malignant neoplasms in Russia in 2020 (morbidity and mortality). ed. by Kaprin AD, Starinsky VV, Shakhzadova AO. M.:P.A. Herzen Moscow state Medical Research Institute - Branch of the Federal state Budgetary Institution NMIC of Radiology of the Ministry of Health of Russia. 2021:252 (In Russ.)].
Коваленко Н.В., Вереникина Е.В., Максимов А.Ю., и др. Прогноз ранних рецидивов рака тела матки на основе мониторинга сывороточных биологических маркеров. Клиническая лабораторная диагностика. 2022;67(4):197203 [Kovalenko NV, Verenikina EV, Maksimov AYu, et al. Prediction of early relapses of uterine body cancer based on monitoring of serum biological markers. Clinical laboratory diagnostics. 2022;67(4):197203 (In Russ.)].
Vermij L, Smit V, Nout R, Bosse T. Incorporation of molecular characteristics into endometrial cancer management. Histopathology. 2020;76(1):5263. doi:10.1111/his.14015.
Winterhoff B, Thomaier L, Mullany S, et al. Molecular characterization of endometrial cancer and therapeutic implications. Curr Opin Obstet Gynecol. 2020;32(1):7683. doi:10.1097/GCO.0000000000000602.
Iunusova NV, Spirina LV, Kondakova LA, et al. Relationship between the expression levels of PAPP-A metalloproteinase and growth and transcriptional factors in endometrial cancer. Izv Akad Nauk Ser Biol. 2013;(3):28491.
Спирина Л.В., Кондакова И.В., Усынин Е.А., и др. Активность протеасом и содержание ростовых факторов при раке почки, мочевого пузыря и эндометрия. Российский онкологический журнал. 2010;(1):235 [Spirina LV, Kondakova IV, Usynin EA, et al. Proteasome activity and content of growth factors in kidney, bladder and endometrial cancer. Russian journal of oncology. 2010;(1):235 (In Russ.)].
Спирина Л.В., Кондакова И.В., Коломиец Л.А., и др. Активность протеасом и их субъединичный состав при гиперпластических процессах и раке эндометрия. Опухоли женской репродуктивной системы. 2011;(4):648 [Spirina LV, Kondakova IV, Kolomiets LA, et al. Activity of proteasomes and their subunit composition in hyperplastic processes and endometrial cancer. Tumors of the female reproductive system. 2011;(4):648 (In Russ.)].
Sahu I, Glickman MH. Structural insights into substrate recognition and processing by the 20s proteasome. Biomolecules. 2021;11(2):148. doi:10.3390/biom11020148.
Ebstein F, Kloetzel PM, Krüger E, et al. Emerging roles of immunoproteasomes beyond MHC class I antigen processing. Cell Mol Life Sci. 2012;69(15):254358. doi:10.1007/s00018-012-0938-0.
Basler M, Groettrup M. On the Role of the Immunoproteasome in Protein Homeostasis. Cells. 2021;10(11):3216. doi:10.3390/cells10113216.
Tertipis N, Haeggblom L, Grün N, et al. Reduced expression of the antigen processing machinery components TAP2, LMP2, and LMP7 in tonsillar and base of tongue cancer and implications for clinical outcome. Transl Oncol. 2015;8(1):10–7. doi:10.1016/j.tranon.2014.11.002.
Ben-Shahar S, Komlosh A, Nadav E, et al. 26 S proteasome-mediated production of an authentic major histocompatibility class I-restricted epitope from an intact protein substrate. J Biol Chem. 1999;274(31):2196372. doi:10.1074/jbc.274.31.21963.
Abbas R, Larisch S. Killing by degradation: regulation of apoptosis by the ubiquitin-proteasome-system. Cells. 2021;10(12):3465. doi:10.3390/cells10123465.
Jiang TX, Ma S, Han X, et al. Proteasome activator PA200 maintains stability of histone marks during transcription and aging. Theranostics. 2021;11(3):14581472. doi:10.7150/thno.48744.
Yen TT, Wang TL, Fader AN, et al. Molecular Classification and Emerging Targeted Therapy in Endometrial Cancer. Int J Gynecol Pathol. 2020;39(1):2635. doi:10.1097/PGP.0000000000000585.
Spirina LV, Bochkareva NV, Kondakova IV, et al. Regulation of insulin-like growth NF-κB proteasome system in endometrial cancer. Mol Biol. 2012;46(3):40713.
Ding F, Xiao H, Wang M, et al. The role of the ubiquitin-proteasome pathway in cancer development and treatment. Front Biosci (Landmark Ed). 2014;19(6):88695. doi:10.2741/4254.
Delle Donne R, Iannucci R, Rinaldi L, et al. Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth. Commun Biol. 2022;5(1):780. doi:10.1038/s42003-022-03639-8.
Wehenkel M, Ban JO, Ho YK, et al. A selective inhibitor of the immunoproteasome subunit LMP2 induces apoptosis in PC-3 cells and suppresses tumour growth in nude mice. Br J Cancer. 2012;107(1):5362. doi:10.1038/bjc.2012.243.
Liu Q, Wang HY, He XJ. Induction of immunoproteasomes in porcine kidney (PK)-15 cells by interferon-γ and tumor necrosis factor-α. J Vet Med Sci. 2019;81(12):177682. doi:10.1292/jvms.19-0157.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
© АННМО «Вопросы онкологии», Copyright (c) 2023