Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press47610.17650/2313-805X-2022-9-4-50-60RESEARCH ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИDiagnostic and prognostic value of long non-coding RNA PROX1‑AS1 and miR-647 expression in gastric cancerДиагностическое и прогностическое значение экспрессии длинной некодирующей РНК PROX1‑AS1 и микроРНК miR-647 при раке желудкаhttps://orcid.org/0000-0001-8069-5540VetchinkinaE. A.ВетчинкинаЕ. А.
Russian Federation

Ekaterina Alexandrovna Vetchinkina

Bld. 2 8 Trubetskaya St., Moscow 119991

Екатерина Александровна Ветчинкина

119991, Москва, ул. Трубецкая, 8, стр. 2

katevetchinkina@ya.ruhttps://orcid.org/0000-0001-9215-4581KalinkinA. I.КалинкинА. И.
Russian Federation

1 Moskvorechye St., Moscow 115522

115522 Москва, ул. Москворечье, 1

https://orcid.org/0000-0001-5825-0430KuznetsovaE. B.КузнецоваЕ. Б.
Russian Federation

Bld. 2 8 Trubetskaya St., Moscow 119991

1 Moskvorechye St., Moscow 115522

119991, Москва, ул. Трубецкая, 8, стр. 2

115522 Москва, ул. Москворечье, 1

https://orcid.org/0000-0002-6930-1261KiselevaA. E.КиселеваА. Э.
Russian Federation

Bld. 2 8 Trubetskaya St., Moscow 119991

119991, Москва, ул. Трубецкая, 8, стр. 2

https://orcid.org/0000-0002-7035-1362AlekseevaE. A.АлексееваЕ. А.
Russian Federation

Bld. 2 8 Trubetskaya St., Moscow 119991

1 Moskvorechye St., Moscow 115522

119991, Москва, ул. Трубецкая, 8, стр. 2

115522 Москва, ул. Москворечье, 1

https://orcid.org/0000-0002-2835-5992NemtsovaM. V.НемцоваМ. В.
Russian Federation

Bld. 2 8 Trubetskaya St., Moscow 119991

1 Moskvorechye St., Moscow 115522

119991, Москва, ул. Трубецкая, 8, стр. 2

115522 Москва, ул. Москворечье, 1

https://orcid.org/0000-0003-2043-5848BureI. V.БуреИ. В.
Russian Federation

Bld. 2 8 Trubetskaya St., Moscow 119991

119991, Москва, ул. Трубецкая, 8, стр. 2

I.M. Sechenov First Moscow State Medical University, Ministry of Health of RussiaФГАОУ ВО Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава РоссииN.P. Bochkov Medical and Genetic Research CenterФГБНУ «Медико-генетический научный центр им. акад. Н. П. Бочкова»15122022941712202217122022Copyright ©; 2022, Vetchinkina E.A., Kalinkin A.I., Kuznetsova E.B., Kiseleva A.E., Alekseeva E.A., Nemtsova M.V., Bure I.V.Copyright ©; 2022, Ветчинкина Е.А., Калинкин А.И., Кузнецова Е.Б., Киселева А.Э., Алексеева Е.А., Немцова М.В., Буре И.В.2022Vetchinkina E.A., Kalinkin A.I., Kuznetsova E.B., Kiseleva A.E., Alekseeva E.A., Nemtsova M.V., Bure I.V.Ветчинкина Е.А., Калинкин А.И., Кузнецова Е.Б., Киселева А.Э., Алексеева Е.А., Немцова М.В., Буре И.В.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/476

Introduction. Gastric cancer remains one of the most common cancers and has a high mortality rate worldwide. Epigenetic alternations of non-coding RNAs (ncRNAs), including microRNAs and long ncRNAs can contribute to its pathogenesis and progression, and could be potent diagnostic and prognostic biomarkers.Aim. Estimation of PROX1‑AS1 and miR-647 expression in gastric cancer and investigation of its clinical significance. Materials and methods. Tumor and adjacent normal tissues (n = 62), and sectional normal tissue samples (n = 5) were included in the study. The expression of the ncRNAs was quantified by reverse transcription-polymerase chain reaction assay.Results. We have reviled the significant difference in the PROX1‑AS1 expression in tumor (p = 0.002) and non-tumor tissues (p <0.001) obtained from gastric cancer patients in comparison with sectional gastric tissues without pathology. Pearson correlation analysis confirmed a negative correlation between PROX1‑AS1 and miR-647 in gastric cancer both in tumor (р <0,001) and adjacent normal tissues (р <0.001). Besides, expression of PROX1‑AS1 and miR-647 was associated with the size and extent of the primary tumor.Conclusion. The obtained results allow to suggest a potential prognostic value of PROX1‑AS1 and miR-647 in gastric cancer.

Введение. Рак желудка входит в число наиболее распространенных злокачественных новообразований и занимает одно из лидирующих мест в структуре смертности от онкологичеких заболеваний во всем мире. Эпигенетические изменения с участием некодирующих РНК (нкРНК), включая микроРНК и длинные нкРНК, вовлечены в его патогенез и прогрессию и могут являться потенциальными диагностическими и прогностическими биомаркерами.Цель исследования – оценить экспрессию PROX1-AS1 и miR-647 при раке желудка и изучить ее клиническое значение.Материалы и методы. В исследование включены 62 парных образца опухоли и неопухолевой ткани желудка, а также 5 секционных образцов ткани желудка без патологии. Анализ экспрессии проведен с помощью метода полимеразной цепной реакции с обратной транскрипцией.Результаты. Обнаружены достоверные различия экспрессии PROX1-AS1 в опухолевых (р = 0,002) и неопухолевых тканях (р <0,001), полученных от пациентов с раком желудка, относительно секционных тканей желудка без патологии. С помощью коэффициента корреляции Пирсона выявлена отрицательная корреляция между экспрессией PROX1-AS1 и miR-647 в опухолевых (р <0,001) и неопухолевых (р <0,001) тканях пациентов с раком желудка. Показано, что экспрессия PROX1-AS1 и miR-647 связана с распространенностью первичной опухоли.Заключение. Полученные результаты позволяют предположить потенциальную прогностическую значимостьPROX1-AS1 и miR-647 при раке желудка.

non-coding RNAslong noncoding RNAmicroRNAgastric cancerepigeneticsbiomarkerнекодирующая РНКдлинная некодирующая РНКмикроРНКрак желудкаэпигенетикабиомаркерThis work was supported by the Russian Science Foundation (grant No. 20-75-10117).Работа выполнена при финансовой поддержке Российского научного фонда (грант № 20-75-10117).1. Sung H., Ferlay J., Siegel R.L. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. Cancer J Clin 2021;71(3): 209–49. DOI: 10.3322/CAAC.21660Sung H., Ferlay J., Siegel R.L. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. Cancer J Clin 2021;71(3): 209–49. DOI: 10.3322/CAAC.216602. Necula L., Matei L., Dragu D. et al. Recent advances in gastric cancer early diagnosis. World J Gastroenterol 2019;25(17):2029–44. DOI: 10.3748/WJG.V25.I17.2029Necula L., Matei L., Dragu D. et al. Recent advances in gastric cancer early diagnosis. World J Gastroenterol 2019;25(17):2029–44. DOI: 10.3748/WJG.V25.I17.20293. Fattani S., Nikbakhsh N., Taheri H. et al. Prevalence of multiple infections and the risk of gastric adenocarcinoma development at earlier age. Diagn Microbiol Infect Dis 2018;92(1):62–8. DOI: 10.1016/J.DIAGMICROBIO.2018.04.015Fattani S., Nikbakhsh N., Taheri H. et al. Prevalence of multiple infections and the risk of gastric adenocarcinoma development at earlier age. Diagn Microbiol Infect Dis 2018;92(1):62–8. DOI: 10.1016/J.DIAGMICROBIO.2018.04.0154. Zhou Z., Lin Z., Pang X. et al. Epigenetic regulation of long noncoding rnas in gastric cancer. Oncotarget 2018;9(27):19443. DOI: 10.18632/ONCOTARGET.23821Zhou Z., Lin Z., Pang X. et al. Epigenetic regulation of long noncoding rnas in gastric cancer. Oncotarget 2018;9(27):19443. DOI: 10.18632/ONCOTARGET.238215. Shi X., Sun M., Liu H. et al. Long non-coding rnas: a new frontier in the study of human diseases. Cancer Lett 2013;339(2):159–66. DOI: 10.1016/J.CANLET.2013.06.013Shi X., Sun M., Liu H. et al. Long non-coding rnas: a new frontier in the study of human diseases. Cancer Lett 2013;339(2):159–66. DOI: 10.1016/J.CANLET.2013.06.0136. Ling H., Fabbri M., Calin G.A. MicroRNAs and other non-coding rnas as targets for anticancer drug development. Nat Rev Drug Discov 2013;12(11):847–65. DOI: 10.1038/NRD4140Ling H., Fabbri M., Calin G.A. MicroRNAs and other non-coding rnas as targets for anticancer drug development. Nat Rev Drug Discov 2013;12(11):847–65. DOI: 10.1038/NRD41407. Rafiee A., Riazi-Rad F., Havaskary M. et al. Long noncoding RNAs: regulation, function and cancer. Biotechnol Genet Eng Rev 2018;34(2):153–80. DOI: 10.1080/02648725.2018.1471566Rafiee A., Riazi-Rad F., Havaskary M. et al. Long noncoding RNAs: regulation, function and cancer. Biotechnol Genet Eng Rev 2018;34(2):153–80. DOI: 10.1080/02648725.2018.14715668. Rawlings-Goss R.A., Campbell M.C., Tishkoff S.A. Global population-specific variation in MiRNA associated with cancer risk and clinical biomarkers. BMC Med Genomics 2014;7(1):53. DOI: 10.1186/1755-8794-7-53Rawlings-Goss R.A., Campbell M.C., Tishkoff S.A. Global population-specific variation in MiRNA associated with cancer risk and clinical biomarkers. BMC Med Genomics 2014;7(1):53. DOI: 10.1186/1755-8794-7-539. Xie S.S., Jin J., Xu X. et al. Emerging roles of non-coding RNAs in gastric cancer: pathogenesis and clinical implications. World J Gastroenterol 2016;22(3):1213–23. DOI: 10.3748/WJG.V22.I3.1213Xie S.S., Jin J., Xu X. et al. Emerging roles of non-coding RNAs in gastric cancer: pathogenesis and clinical implications. World J Gastroenterol 2016;22(3):1213–23. DOI: 10.3748/WJG.V22.I3.121310. Yang F., Bi J., Xue X. et al. Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS J 2012;279(17):3159–65. DOI: 10.1111/J.1742-4658.2012.08694.XYang F., Bi J., Xue X. et al. Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS J 2012;279(17):3159–65. DOI: 10.1111/J.1742-4658.2012.08694.X11. Sun M., Xia R., Jin F. et al. Downregulated long noncoding RNA MEG3 Is associated with poor prognosis and promotes cell proliferation in gastric cancer. Tumour Biol 2014;35(2):1065–73. DOI: 10.1007/S13277-013-1142-ZSun M., Xia R., Jin F. et al. Downregulated long noncoding RNA MEG3 Is associated with poor prognosis and promotes cell proliferation in gastric cancer. Tumour Biol 2014;35(2):1065–73. DOI: 10.1007/S13277-013-1142-Z12. Jiang W., Meng K., Yang T. Long non-coding RNA PROX1-AS1 promotes the proliferation and migration in gastric cancer by epigenetically activating FGFR1. Panminerva Med 2019. Available at: https://pubmed.ncbi.nlm.nih.gov/31355614/Jiang W., Meng K., Yang T. Long non-coding RNA PROX1-AS1 promotes the proliferation and migration in gastric cancer by epigenetically activating FGFR1. Panminerva Med 2019. Available at: https://pubmed.ncbi.nlm.nih.gov/31355614/13. Rudzinska M., Czarnecka-Chrebelska K.H., Kuznetsova E.B. et al. Long non-coding PROX1-AS1 expression correlates with renal cell carcinoma metastasis and aggressiveness. Non-Coding RNA 2021;7(2):25. DOI: 10.3390/NCRNA7020025Rudzinska M., Czarnecka-Chrebelska K.H., Kuznetsova E.B. et al. Long non-coding PROX1-AS1 expression correlates with renal cell carcinoma metastasis and aggressiveness. Non-Coding RNA 2021;7(2):25. DOI: 10.3390/NCRNA702002514. Tu B., Ye L., Cao Q. et al. Identification of a five-MiRNA signature as a novel potential prognostic biomarker in patients with nasopharyngeal carcinoma. Hereditas 2022;159(1):3. DOI: 10.1186/S41065-021-00214-9Tu B., Ye L., Cao Q. et al. Identification of a five-MiRNA signature as a novel potential prognostic biomarker in patients with nasopharyngeal carcinoma. Hereditas 2022;159(1):3. DOI: 10.1186/S41065-021-00214-915. Ye X., Qiu R., He X. et al. MiR-647 Inhibits hepatocellular carcinoma cell progression by targeting protein tyrosine phosphatase receptor type F. Bioengineered 2022;13(1):1090–102. DOI: 10.1080/21655979.2021.2017628Ye X., Qiu R., He X. et al. MiR-647 Inhibits hepatocellular carcinoma cell progression by targeting protein tyrosine phosphatase receptor type F. Bioengineered 2022;13(1):1090–102. DOI: 10.1080/21655979.2021.201762816. Liu S., Qu D., Li W. et al. MiR-647 and MiR-1914 promote cancer progression equivalently by downregulating nuclear factor IX in colorectal cancer. Mol Med Rep 2017;16(6):8189–99. DOI: 10.3892/MMR.2017.7675/HTMLLiu S., Qu D., Li W. et al. MiR-647 and MiR-1914 promote cancer progression equivalently by downregulating nuclear factor IX in colorectal cancer. Mol Med Rep 2017;16(6):8189–99. DOI: 10.3892/MMR.2017.7675/HTML17. Zhang X., Zhang M., Wang G. et al. Tumor promoter role of MiR-647 in gastric cancer via repression of TP73. Mol Med Rep 2018;18(4):3744–50. DOI: 10.3892/MMR.2018.9358Zhang X., Zhang M., Wang G. et al. Tumor promoter role of MiR-647 in gastric cancer via repression of TP73. Mol Med Rep 2018;18(4):3744–50. DOI: 10.3892/MMR.2018.935818. Ma H., Wang P., Li Y. et al. Decreased expression of serum MiR-647 is associated with poor prognosis in gastric cancer. Int J Clin Exp Pathol 2019;12(7):2552–8.Ma H., Wang P., Li Y. et al. Decreased expression of serum MiR-647 is associated with poor prognosis in gastric cancer. Int J Clin Exp Pathol 2019;12(7):2552–8.19. Song X., Bi Y., Guo W. Long noncoding RNA PROX1-AS1 promotes tumor progression and aggressiveness by sponging MiR-647 in gastric cancer. Minerva Med 2021;112(3):421–3. DOI: 10.23736/S0026-4806.19.06223-2Song X., Bi Y., Guo W. Long noncoding RNA PROX1-AS1 promotes tumor progression and aggressiveness by sponging MiR-647 in gastric cancer. Minerva Med 2021;112(3):421–3. DOI: 10.23736/S0026-4806.19.06223-220. Biomedical Informatics Institute. Available at: https://bioinfo.henu.edu.cn/DatabaseList.jsp.Biomedical Informatics Institute. Available at: https://bioinfo.henu.edu.cn/DatabaseList.jsp.21. Barrett T., Wilhite S.E., Ledoux P. et al. NCBI GEO: archive for functional genomics data sets-update. Nucleic Acids Res 2013;41(D1):D991–5. DOI: 10.1093/NAR/GKS1193Barrett T., Wilhite S.E., Ledoux P. et al. NCBI GEO: archive for functional genomics data sets-update. Nucleic Acids Res 2013;41(D1):D991–5. DOI: 10.1093/NAR/GKS119322. Qian Z., Zhu G., Tang L. et al. Whole genome gene copy number profiling of gastric cancer identifies PAK1 and KRAS gene amplification as therapy targets. Genes Chromosom Cancer 2014;53(11):883–94. DOI: 10.1002/GCC.22196Qian Z., Zhu G., Tang L. et al. Whole genome gene copy number profiling of gastric cancer identifies PAK1 and KRAS gene amplification as therapy targets. Genes Chromosom Cancer 2014;53(11):883–94. DOI: 10.1002/GCC.2219623. GEO Accession viewer. Available at: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57303.GEO Accession viewer. Available at: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57303.24. Bure I.V., Nemtsova M.V. Methylation and noncoding RNAs in gastric cancer: everything is connected. Int J Mol Sci 2021;22(11):5683. DOI: 10.3390/IJMS22115683Bure I.V., Nemtsova M.V. Methylation and noncoding RNAs in gastric cancer: everything is connected. Int J Mol Sci 2021;22(11):5683. DOI: 10.3390/IJMS2211568325. LncACTdb 3.0: Home. Available at: http://bio-bigdata.hrbmu.edu.cn/LncACTdb/.LncACTdb 3.0: Home. Available at: http://bio-bigdata.hrbmu.edu.cn/LncACTdb/.26. Shen Y., Xia E., Bhandari A. et al. LncRNA PROX1-AS1 promotes proliferation, invasion, and migration in papillary thyroid carcinoma. Biosci Rep 2018;38(5):BSR20180862. DOI: 10.1042/BSR20180862Shen Y., Xia E., Bhandari A. et al. LncRNA PROX1-AS1 promotes proliferation, invasion, and migration in papillary thyroid carcinoma. Biosci Rep 2018;38(5):BSR20180862. DOI: 10.1042/BSR2018086227. Chen Y., Lu B., Liu L. et al. Long non-coding RNA PROX1-AS1 knockdown upregulates microRNA-519d-3p to promote chemosensitivity of retinoblastoma cells via targeting SOX2. Cell Cycle 2021;20(20):2149–59. DOI: 10.1080/15384101.2021.1971352Chen Y., Lu B., Liu L. et al. Long non-coding RNA PROX1-AS1 knockdown upregulates microRNA-519d-3p to promote chemosensitivity of retinoblastoma cells via targeting SOX2. Cell Cycle 2021;20(20):2149–59. DOI: 10.1080/15384101.2021.197135228. Guo T., Wang W., Ji Y. et al. LncRNA PROX1-AS1 facilitates gastric cancer progression via miR-877-5p/PD-L1 Axis. Cancer Manag Res 2021;13:2669. DOI: 10.2147/CMAR.S275352Guo T., Wang W., Ji Y. et al. LncRNA PROX1-AS1 facilitates gastric cancer progression via miR-877-5p/PD-L1 Axis. Cancer Manag Res 2021;13:2669. DOI: 10.2147/CMAR.S27535229. Qin K., Tian G., Chen G. et al. MiR-647 inhibits glioma cell proliferation, colony formation and invasion by regulating HOXA9. J Gene Med 2020;22(3):e3153. DOI: 10.1002/JGM.3153Qin K., Tian G., Chen G. et al. MiR-647 inhibits glioma cell proliferation, colony formation and invasion by regulating HOXA9. J Gene Med 2020;22(3):e3153. DOI: 10.1002/JGM.315330. Zhang Y.S., Chen T., Cai Y.J. et al. MicroRNA-647 promotes the therapeutic effectiveness of argon-helium cryoablation and inhibits cell proliferation through targeting TRAF2 via the NF-ΚB signaling pathway in non-small cell lung cancer. Onco Targets Ther 2018;11:6777–84. DOI: 10.2147/OTT.S159337Zhang Y.S., Chen T., Cai Y.J. et al. MicroRNA-647 promotes the therapeutic effectiveness of argon-helium cryoablation and inhibits cell proliferation through targeting TRAF2 via the NF-ΚB signaling pathway in non-small cell lung cancer. Onco Targets Ther 2018;11:6777–84. DOI: 10.2147/OTT.S15933731. Du L., Wang X., Yin Y. et al. Identification of a potentially functional circRNA-miRNA-mRNA ceRNA regulatory network in bladder cancer by analysis of microarray data. Transl Androl Urol 2021;10(1):24–36. DOI: 10.21037/TAU-20-660Du L., Wang X., Yin Y. et al. Identification of a potentially functional circRNA-miRNA-mRNA ceRNA regulatory network in bladder cancer by analysis of microarray data. Transl Androl Urol 2021;10(1):24–36. DOI: 10.21037/TAU-20-66032. Cao W., Wei W., Zhan Z. et al. Role of miR-647 in human gastric cancer suppression. Oncol Rep 2017;37(3):1401–11. DOI: 10.3892/OR.2017.5383Cao W., Wei W., Zhan Z. et al. Role of miR-647 in human gastric cancer suppression. Oncol Rep 2017;37(3):1401–11. DOI: 10.3892/OR.2017.538333. Yang B., Jing C., Wang J. et al. Identification of microRNAs associated with lymphangiogenesis in human gastric cancer. Clin Transl Oncol 2014;16(4):374–9. DOI: 10.1007/S12094-013-1081-6Yang B., Jing C., Wang J. et al. Identification of microRNAs associated with lymphangiogenesis in human gastric cancer. Clin Transl Oncol 2014;16(4):374–9. DOI: 10.1007/S12094-013-1081-634. Zhao Q., Zhang B., Li Z. et al. Effects of incRNA PROX1-AS1 on proliferation, migration, invasion and apoptosis of lung cancer cells by regulating miR-1305. J Healthc Eng 2022;2022:9570900. DOI: 10.1155/2022/9570900Zhao Q., Zhang B., Li Z. et al. Effects of incRNA PROX1-AS1 on proliferation, migration, invasion and apoptosis of lung cancer cells by regulating miR-1305. J Healthc Eng 2022;2022:9570900. DOI: 10.1155/2022/9570900