mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-MAT-3150mimmun-3150Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESМикроРНК и гены-мишени как регуляторы иммунных сигнальных механизмов рака толстой кишкиMicroRNAs and target genes as regulators of colon cancer immune signalinghttps://orcid.org/0000-0003-3061-6108КитО. И.KitO. I.

Кит Олег Иванович – д.м.н., профессор, академик РАН, генеральный директор 

Ростов-на-Дону

Kit Oleg I., PhD, MD (Medicine), Professor, Full Member, Russian Academy of Sciences, General Director

Rostov-on-Don

onko-sekretar@mail.ruhttps://orcid.org/0000-0001-8633-2660ГвалдинД. Ю.GvaldinD. Yu.

Гвалдин Дмитрий Юрьевич – к.б.н., научный сотрудник лаборатории молекулярной онкологии 

Ростов-на-Дону

Gvaldin Dmitriy Yu., PhD (Biology), Researcher, Laboratory of Molecular Oncology

Rostov-on-Don

89dmitry@mail.ruhttps://orcid.org/0000-0001-7919-6111ПетрусенкоН. А.PetrusenkoN. A.

Петрусенко Наталья Александровна – младший научный сотрудник лаборатории молекулярной онкологии 

Ростов-на-Дону

Petrusenko Natalia A., Junior Researcher, Laboratory of Molecular Oncology

Rostov-on-Don

petrusenko-natulya@mail.ruhttps://orcid.org/0000-0001-6358-7361ТимошкинаН. Н.TimoshkinaN. N.

Тимошкина Наталья Николаевна – к.б.н., заведующая лабораторией молекулярной онкологии 

Ростов-на-Дону

Timoshkina Natalia N., PhD (Biology), Head, Laboratory of Molecular Oncology

Rostov-on-Don

timoshkinann@rnioi.ruhttps://orcid.org/0000-0002-2496-2728СавченкоД. А.SavchenkoD. A.

Савченко Дмитрий Александрович – врач-онколог 

Ростов-на-Дону

Savchenko Dmitry A., Clinical Oncologist

Rostov-on-Don

doc.sav.rnd@gmail.comhttps://orcid.org/0000-0002-6496-9641НовиковаИ. А.NovikovaI. A.

Новикова Инна Арнольдовна – д.м.н., заместитель генерального директора по науке 

Ростов-на-Дону

Novikova Inna A., PhD, MD (Medicine), Deputy Director for Research

Rostov-on-Don

novikovainna@yahoo.comФГБУ «Национальный медицинский исследовательский центр онкологии» Министерства здравоохранения РФРоссияNational Medical Research Centre for OncologyRussian Federation202507072025274775788Copyright © Кит О.И., Гвалдин Д.Ю., Петрусенко Н.А., Тимошкина Н.Н., Савченко Д.А., Новикова И.А., 20252025Кит О.И., Гвалдин Д.Ю., Петрусенко Н.А., Тимошкина Н.Н., Савченко Д.А., Новикова И.А.Kit O.I., Gvaldin D.Y., Petrusenko N.A., Timoshkina N.N., Savchenko D.A., Novikova I.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/3150

Колоректальный рак (КРР) относится к числу наиболее распространенных онкозаболеваний в мире, сопряженных с высоким уровнем смертности. В последнее время получили развитие имуннотерапевтические подходы лечения КРР, которые позволили добиться длительной и стойкой ремиссии у определенной группы больных. Успех иммунотерапии зависит от иммунных процессов, сопряженных с онкогенезом в толстой кишке. Ключевую роль в модуляции иммунного окружения опухоли играет активность генов, регулирующих дифференцировку и функции иммунных клеток, а также пул микроРНК, осуществляющих посттранскрипционный контроль экспрессии генов-мишеней. В связи с этим целью нашей работы являлось исследование экспрессионных профилей иммунно-ассоциированных генов и микроРНК для определения иммунных сигнальных механизмов рака толстой кишки и поиска потенциальных терапевтических мишеней. В исследование вошли 18 человек (12 женщин, 6 мужчин, медиана возраста – 66 лет) с диагнозом «ЗНО толстой кишки», проходивших лечение на базе ФГБУ «НМИЦ онкологии» в 2018-2019 гг. Все опухоли имели статус микросателлитной нестабильности. Транскрипционные профили микроРНК и генов иммунного ответа были определены методом секвенирования следующего поколения. По результатам исследования, количество дифференциально экспрессирующихся в опухоли микроРНК составило 28, из них 15 микроРНК с повышенной экспрессией и 13 микроРНК с пониженной экспрессией. Из 395 исследованных генов дифференциально экспрессирующимися были 156, среди которых 62 гена обладали повышенной экспрессией и 94 – пониженной. Идентификация клеточных популяций на основании транскрипционного паттерна опухолей выявила присутствие 4 типов иммунных клеток: нейтрофилы, B-лимфоциты, CD8+Т-лимфоциты и макрофаги М1. Нейтрофилы оказались наиболее распространенным типом клеток (16 из 18 образцов). Поэтапный анализ наличия возможных связей между транскрипционными паттернами позволил отобрать 713 пар микроРНК-мРНК. После фильтрации по валидированным взаимодействиям количество пар составило 24, на основании чего была сконструирована сеть взаимодействий микроРНК-мРНК, которая участвовала в регуляции множества иммунных сигнальных механизмов и контроля клеточного цикла. В большинстве выделенных сигналингах присутствовал CDK1, для которого известны доступные терапевтические ингибиторы, находящиеся на разных этапах клинических испытаний. Описанные в работе возможности воздействия на CDK1 могут послужить заделом для дальнейших клинических исследований и разработке терапевтических стратегий, основанных на молекулярно-селективном подавлении иммунных механизмов онкогенеза колоректального рака.

Colorectal cancer (CRC) is among the most common oncological diseases in the world, associated with a high mortality rate. Recently, immunotherapeutic approaches to the treatment of CRC have been developed, which have enabled achievement of long-term and stable remission in a certain group of patients. The success of immunotherapy depends on the immune processes associated with oncogenesis in the colon. The key role in modulating immune environment of the tumor is played by the activity of genes regulating differentiation and functions of immune cells, as well as by a variety of microRNAs that perform posttranscriptional expression control of target genes. In this regard, the aim of our work was to study the expression profiles of immune-associated genes and microRNAs to determine the immune signaling mechanisms of colon cancer and search for potential therapeutic targets. The study included 18 persons (12 women, 6 men, median age – 66 years) diagnosed with colon cancer, having been treated at the National Medical Research Center of Oncology in 2018-2019. All tumors had microsatellite instability status. The transcription profiles of microRNAs and immune response genes were determined by next-generation sequencing. The study has revealed 28 differentially expressed microRNAs in the tumor tissues, including 15 microRNAs with increased expression and 13 microRNAs with decreased expression. Of the 395 genes examined, 156 were differentially expressed, including 62 genes with increased expression and 94 genes with decreased activity. Identification of cell populations based on the transcriptional pattern of tumors has discerned four types of immune cells: neutrophils, B lymphocytes, CD8+T lymphocytes, and M1 macrophages. Neutrophils were the most common cell type (16 of 18 samples). A stepwise analysis of possible relationships between transcriptional patterns allowed us to select 713 miRNA-mRNA pairs. After filtering by validated interactions, 24 such pairs were found. On this basis, a miRNA-mRNA interaction network was constructed, which could be involved into the regulation of multiple immune signaling mechanisms and cell cycle control. Most of the revealed signaling pathways contained CDK1, for which therapeutic inhibitors are known, being at different stages of clinical trials. The possibilities of influencing CDK1 described in the present work may be used for further clinical studies and development of therapeutic strategies employing selective molecular suppression of immunemediated carcinogenesis in colorectal cancer.

транскриптоммикроРНКиммунное микроокружениеколоректальный ракNGSCDK1таргетная терапияtranscriptomemicroRNAimmune microenvironmentcolorectal cancerNGSCDK1targeted therapyReferencesКит О.И., Дженкова Е.А., Мирзоян Э.А., Геворкян Ю.А., Сагакянц А.Б., Тимошкина Н.Н., Каймакчи О.Ю., Каймакчи Д.О., Толмах Р.Е., Дашков А.В., Колесников В.Е., Милакин А.Г., Полуэктов С.И. Молекулярно-генетическая классификация подтипов колоректального рака: современное состояние проблемы // Южно-Российский онкологический журнал, 2021. Т. 2, № 2. С. 50-56.Kit O.I., Dzhenkova E.A., Mirzoyan E.A., Gevorkyan Yu.A., Sagakyants A.B., Timoshkina N.N., Kaymakchi O.Yu., Kaymakchi D.O., Tolmakh R.E., Dashkov A.V., Kolesnikov V.E., Milakin A.G., Poluektov S.I. Molecular genetic classification of colorectal cancer subtypes: current state of the problem. Yuzhno-Rossiyskiy onkologicheskiy zhurnal = South Russian Journal of Cancerm 2021, Vol. 2, no. 2, pp. 50-56. (In Russ.)Максимова П.Е., Голубинская Е.П., Сеферов Б.Д., Зяблицкая Е.Ю. Колоректальный рак: эпидемиология, канцерогенез, молекулярно-генетические и клеточные механизмы резистентности к терапии (аналитический обзор) // Колопроктология, 2023. Т. 22, № 2. С. 160-171.Maksimova P.E., Golubinskaya E.P., Seferov B.D., Zyablitska E.Yu. Colorectal cancer: epidemiology, carcinogenesis, molecular subtypes and cellular mechanisms of therapy resistance (analytical review). Koloproktologiya = Koloproktologia, 2023, Vol. 22, no. 2, pp. 160-171. (In Russ.)Ahmadi S.E., Rahimi S., Zarandi B., Chegeni R., Safa M. MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies. J. Hematol Oncol., 2021, Vol. 14, no. 1, 121. doi: 10.1186/s13045-021-01111-4.Ahmadi S.E., Rahimi S., Zarandi B., Chegeni R., Safa M. MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies. J. Hematol Oncol., 2021, Vol. 14, no. 1, 121. doi: 10.1186/s13045-021-01111-4.Amicarella F., Muraro M.G., Hirt C., Cremonesi E., Padovan E., Mele V., Governa V., Han J., Huber X., Droeser R.A., Zuber M., Adamina M., Bolli M., Rosso R., Lugli A., Zlobec I., Terracciano L., Tornillo L., Zajac P., Eppenberger-Castori S., Trapani F., Oertli D., Iezzi G. Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer. Gut, 2017, Vol. 66, no. 4, pp. 692-704.Amicarella F., Muraro M.G., Hirt C., Cremonesi E., Padovan E., Mele V., Governa V., Han J., Huber X., Droeser R.A., Zuber M., Adamina M., Bolli M., Rosso R., Lugli A., Zlobec I., Terracciano L., Tornillo L., Zajac P., Eppenberger-Castori S., Trapani F., Oertli D., Iezzi G. Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer. Gut, 2017, Vol. 66, no. 4, pp. 692-704.Bai Z., Zhou Y., Ye Z., Xiong J., Lan H., Wang F. Tumor-infiltrating lymphocytes in colorectal cancer: the fundamental indication and application on immunotherapy. Front. Immunol., 2022, Vol. 12, 808964. doi: 10.3389/fimmu.2021.808964.Bai Z., Zhou Y., Ye Z., Xiong J., Lan H., Wang F. Tumor-infiltrating lymphocytes in colorectal cancer: the fundamental indication and application on immunotherapy. Front. Immunol., 2022, Vol. 12, 808964. doi: 10.3389/fimmu.2021.808964.Bednarz-Misa I., Bromke M.A., Krzystek-Korpacka M. Interleukin (IL)-7 signaling in the tumor microenvironment. Adv. Exp. Med. Biol., 2021, Vol. 1290, pp. 9-49.Bednarz-Misa I., Bromke M.A., Krzystek-Korpacka M. Interleukin (IL)-7 signaling in the tumor microenvironment. Adv. Exp. Med. Biol., 2021, Vol. 1290, pp. 9-49.Coker E.A., Mitsopoulos C., Tym J.E., Komianou A., Kannas C., Di Micco P., Villasclaras Fernandez E., Ozer B., Antolin A.A., Workman P., Al-Lazikani B. canSAR: update to the cancer translational research and drug discovery knowledgebase. Nucleic Acids Res., 2019, Vol. 47, pp. D917-D922.Coker E.A., Mitsopoulos C., Tym J.E., Komianou A., Kannas C., Di Micco P., Villasclaras Fernandez E., Ozer B., Antolin A.A., Workman P., Al-Lazikani B. canSAR: update to the cancer translational research and drug discovery knowledgebase. Nucleic Acids Res., 2019, Vol. 47, pp. D917-D922.Ding X., Duan H., Luo H. Identification of core gene expression signature and key pathways in colorectal cancer. Front. Genet., 2020, Vol. 11, 45. doi: 10.3389/fgene.2020.00045.Ding X., Duan H., Luo H. Identification of core gene expression signature and key pathways in colorectal cancer. Front. Genet., 2020, Vol. 11, 45. doi: 10.3389/fgene.2020.00045.Fu C., Zhang X., Zhang X., Wang D., Han S., Ma Z. Advances in IL-7 research on tumour therapy. Pharmaceuticals (Basel), 2024, Vol. 17, no. 4, 415. doi: 10.3390/ph17040415.Fu C., Zhang X., Zhang X., Wang D., Han S., Ma Z. Advances in IL-7 research on tumour therapy. Pharmaceuticals (Basel), 2024, Vol. 17, no. 4, 415. doi: 10.3390/ph17040415.Gherman A., Bolundut D., Ecea R., Balacescu L., Curcean S., Dina C., Balacescu O., Cainap C. Molecular subtypes, microRNAs and immunotherapy response in metastatic colorectal cancer. Medicina (Kaunas), 2024, Vol. 60, no. 3, 397. doi: 10.3390/medicina60030397.Gherman A., Bolundut D., Ecea R., Balacescu L., Curcean S., Dina C., Balacescu O., Cainap C. Molecular subtypes, microRNAs and immunotherapy response in metastatic colorectal cancer. Medicina (Kaunas), 2024, Vol. 60, no. 3, 397. doi: 10.3390/medicina60030397.Guo N., Shen G., Zhang Y., Moustafa A.A., Ge D., You Z. Interleukin-17 promotes migration and invasion of human cancer cells through upregulation of MTA1 expression. Front. Oncol., 2019, Vol. 9, 546. doi: 10.3389/fonc.2019.00546.Guo N., Shen G., Zhang Y., Moustafa A.A., Ge D., You Z. Interleukin-17 promotes migration and invasion of human cancer cells through upregulation of MTA1 expression. Front. Oncol., 2019, Vol. 9, 546. doi: 10.3389/fonc.2019.00546.Han L., Chen S., Luan Z., Fan M., Wang Y., Sun G., Dai G. Immune function of colon cancer associated miRNA and target genes. Front. Immunol., 2023, Vol. 14, 1203070. doi: 10.3389/fimmu.2023.1203070.Han L., Chen S., Luan Z., Fan M., Wang Y., Sun G., Dai G. Immune function of colon cancer associated miRNA and target genes. Front. Immunol., 2023, Vol. 14, 1203070. doi: 10.3389/fimmu.2023.1203070.Hao M., Li H., Yi M., Zhu Y., Wang K., Liu Y., Liang X., Ding L. Development of an immune-related gene prognostic risk model and identification of an immune infiltration signature in the tumor microenvironment of colon cancer. BMC Gastroenterol., 2023, Vol. 23, no. 1, 58. doi: 10.1186/s12876-023-02679-6.Hao M., Li H., Yi M., Zhu Y., Wang K., Liu Y., Liang X., Ding L. Development of an immune-related gene prognostic risk model and identification of an immune infiltration signature in the tumor microenvironment of colon cancer. BMC Gastroenterol., 2023, Vol. 23, no. 1, 58. doi: 10.1186/s12876-023-02679-6.Holubekova V., Loderer D., Grendar M., Mikolajcik P., Kolkova Z., Turyova E., Kudelova E., Kalman M., Marcinek J., Miklusica J., Laca L., Lasabova Z. Differential gene expression of immunity and inflammation genes in colorectal cancer using targeted RNA sequencing. Front. Oncol., 2023, Vol. 13, 1206482. doi: 10.3389/fonc.2023.1206482.Holubekova V., Loderer D., Grendar M., Mikolajcik P., Kolkova Z., Turyova E., Kudelova E., Kalman M., Marcinek J., Miklusica J., Laca L., Lasabova Z. Differential gene expression of immunity and inflammation genes in colorectal cancer using targeted RNA sequencing. Front. Oncol., 2023, Vol. 13, 1206482. doi: 10.3389/fonc.2023.1206482.Jiang J.K., Lin C.H., Chang T.A., Lo L.C., Lin C.P., Lu R.H., Yang C.Y. Decreased interleukin-17RA expression is associated with good prognosis in patients with colorectal cancer and inhibits tumor growth and vascularity in mice. Cancer Med., 2024, Vol. 13, no. 5, e7059. doi: 10.1002/cam4.7059.Jiang J.K., Lin C.H., Chang T.A., Lo L.C., Lin C.P., Lu R.H., Yang C.Y. Decreased interleukin-17RA expression is associated with good prognosis in patients with colorectal cancer and inhibits tumor growth and vascularity in mice. Cancer Med., 2024, Vol. 13, no. 5, e7059. doi: 10.1002/cam4.7059.Jordakieva G., Bianchini R., Reichhold D., Piehslinger J., Groschopf A., Jensen S.A., Mearini E., Nocentini G., Crevenna R., Zlabinger G.J., Karagiannis S.N., Klaus A., Jensen-Jarolim E. IgG4 induces tolerogenic M2-like macrophages and correlates with disease progression in colon cancer. Oncoimmunology, 2021, Vol. 10, no. 1, 1880687. doi: 10.1080/2162402X.2021.1880687.Jordakieva G., Bianchini R., Reichhold D., Piehslinger J., Groschopf A., Jensen S.A., Mearini E., Nocentini G., Crevenna R., Zlabinger G.J., Karagiannis S.N., Klaus A., Jensen-Jarolim E. IgG4 induces tolerogenic M2-like macrophages and correlates with disease progression in colon cancer. Oncoimmunology, 2021, Vol. 10, no. 1, 1880687. doi: 10.1080/2162402X.2021.1880687.Kim J.H., Seo M.K., Lee J.A., Yoo S.Y., Oh H.J., Kang H., Cho N.Y., Bae J.M., Kang G.H., Kim S. Genomic and transcriptomic characterization of heterogeneous immune subgroups of microsatellite instability-high colorectal cancers. J. Immunother. Cancer, 2021, Vol. 9, no. 12, e003414. doi: 10.1136/jitc-2021-003414.Kim J.H., Seo M.K., Lee J.A., Yoo S.Y., Oh H.J., Kang H., Cho N.Y., Bae J.M., Kang G.H., Kim S. Genomic and transcriptomic characterization of heterogeneous immune subgroups of microsatellite instability-high colorectal cancers. J. Immunother. Cancer, 2021, Vol. 9, no. 12, e003414. doi: 10.1136/jitc-2021-003414.Koelzer V.H., Canonica K., Dawson H., Sokol L., Karamitopoulou-Diamantis E., Lugli A., Zlobec I. Phenotyping of tumor-associated macrophages in colorectal cancer: Impact on single cell invasion (tumor budding) and clinicopathological outcome. Oncoimmunology, 2015, Vol. 5, no. 4, e1106677. doi: 10.1080/2162402X.2015.1106677.Koelzer V.H., Canonica K., Dawson H., Sokol L., Karamitopoulou-Diamantis E., Lugli A., Zlobec I. Phenotyping of tumor-associated macrophages in colorectal cancer: Impact on single cell invasion (tumor budding) and clinicopathological outcome. Oncoimmunology, 2015, Vol. 5, no. 4, e1106677. doi: 10.1080/2162402X.2015.1106677.Konstantinov A.S., Kovaleva O.V., Samoilova D.V., Shelekhova K.V. Role of macrophages in progression of colorectal cancer: a contrast with the traditional paradigm. Int. J. Clin. Exp. Pathol., 2022, Vol. 15, no. 10, pp. 403-411.Konstantinov A.S., Kovaleva O.V., Samoilova D.V., Shelekhova K.V. Role of macrophages in progression of colorectal cancer: a contrast with the traditional paradigm. Int. J. Clin. Exp. Pathol., 2022, Vol. 15, no. 10, pp. 403-411.Kuhn M., von Mering C., Campillos M., Jensen L.J., Bork P. STITCH: interaction networks of chemicals and proteins. Nucleic Acids Res., 2008, Vol. 36, pp. D684-D688.Kuhn M., von Mering C., Campillos M., Jensen L.J., Bork P. STITCH: interaction networks of chemicals and proteins. Nucleic Acids Res., 2008, Vol. 36, pp. D684-D688.Le T.D., Zhang J., Liu L., Liu H., Li J. miRLAB: An R based dry lab for exploring miRNA-mRNA regulatory relationships. PLoS One, 2015, Vol. 10, no. 12, e0145386. doi: 10.1371/journal.pone.0145386.Le T.D., Zhang J., Liu L., Liu H., Li J. miRLAB: An R based dry lab for exploring miRNA-mRNA regulatory relationships. PLoS One, 2015, Vol. 10, no. 12, e0145386. doi: 10.1371/journal.pone.0145386.Li J., Wang Y., Wang X., Yang Q. CDK1 and CDC20 overexpression in patients with colorectal cancer are associated with poor prognosis: evidence from integrated bioinformatics analysis. World J. Surg. Oncol., 2020, Vol. 18, no. 1, 50. doi: 10.1186/s12957-020-01817-8.Li J., Wang Y., Wang X., Yang Q. CDK1 and CDC20 overexpression in patients with colorectal cancer are associated with poor prognosis: evidence from integrated bioinformatics analysis. World J. Surg. Oncol., 2020, Vol. 18, no. 1, 50. doi: 10.1186/s12957-020-01817-8.Love M.I., Huber W., Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 2014, Vol. 15, no. 12, 550. doi: 10.1186/s13059-014-0550-8.Love M.I., Huber W., Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 2014, Vol. 15, no. 12, 550. doi: 10.1186/s13059-014-0550-8.Marini F., Finotello F. quantiseqr: Quantification of the Tumor Immune contexture from RNA-seq data. 2023. Available at: https://bioconductor.org/packages/release/bioc/html/quantiseqr.html.Marini F., Finotello F. quantiseqr: Quantification of the Tumor Immune contexture from RNA-seq data. 2023. Available at: https://bioconductor.org/packages/release/bioc/html/quantiseqr.html.Ogawa R., Yamamoto T., Hirai H., Hanada K., Kiyasu Y., Nishikawa G., Mizuno R., Inamoto S., Itatani Y., Sakai Y., Kawada K. Loss of SMAD4 promotes colorectal cancer progression by recruiting tumor-associated neutrophils via the CXCL1/8-CXCR2 Axis. Clin. Cancer Res., 2019, Vol. 25, no. 9, pp. 2887-2899. doi: 10.1158/1078-0432.CCR-18-3684.Ogawa R., Yamamoto T., Hirai H., Hanada K., Kiyasu Y., Nishikawa G., Mizuno R., Inamoto S., Itatani Y., Sakai Y., Kawada K. Loss of SMAD4 promotes colorectal cancer progression by recruiting tumor-associated neutrophils via the CXCL1/8-CXCR2 Axis. Clin. Cancer Res., 2019, Vol. 25, no. 9, pp. 2887-2899. doi: 10.1158/1078-0432.CCR-18-3684.Pieniadz P., Piet M., Paduch R. Characteristics of the colorectal cancer microenvironment – role in cancer progression and therapeutic possibilities. Appl. Sci., 2024, Vol. 14, no. 7, 2930. doi: 10.3390/app14072930.Pieniadz P., Piet M., Paduch R. Characteristics of the colorectal cancer microenvironment – role in cancer progression and therapeutic possibilities. Appl. Sci., 2024, Vol. 14, no. 7, 2930. doi: 10.3390/app14072930.Rajtmajerová M., Trailin A., Liška V., Hemminki K., Ambrozkiewicz F. Long Non-Coding RNA and microRNA interplay in colorectal cancer and their effect on the tumor microenvironment. Cancers (Basel), 2022, Vol. 14, no. 21, 5450. doi: 10.3390/cancers14215450.Rajtmajerová M., Trailin A., Liška V., Hemminki K., Ambrozkiewicz F. Long Non-Coding RNA and microRNA interplay in colorectal cancer and their effect on the tumor microenvironment. Cancers (Basel), 2022, Vol. 14, no. 21, 5450. doi: 10.3390/cancers14215450.Razi S., Baradaran Noveiry B., Keshavarz-Fathi M., Rezaei N. IL-17 and colorectal cancer: From carcinogenesis to treatment. Cytokine, 2019, Vol. 116, pp. 7-12.Razi S., Baradaran Noveiry B., Keshavarz-Fathi M., Rezaei N. IL-17 and colorectal cancer: From carcinogenesis to treatment. Cytokine, 2019, Vol. 116, pp. 7-12.Rodriguez C., Araujo Furlan C.L., Tosello Boari J., Bossio S.N., Boccardo S., Fozzatti L., Canale F.P., Beccaria C.G., Nuñez N.G., Ceschin D.G., Piaggio E., Gruppi A., Montes C.L., Acosta Rodríguez E.V. Interleukin-17 signaling influences CD8+ T cell immunity and tumor progression according to the IL-17 receptor subunit expression pattern in cancer cells. Oncoimmunology, 2023, Vol. 12, no. 1, 2261326. doi: 10.1080/2162402X.2023.2261326.Rodriguez C., Araujo Furlan C.L., Tosello Boari J., Bossio S.N., Boccardo S., Fozzatti L., Canale F.P., Beccaria C.G., Nuñez N.G., Ceschin D.G., Piaggio E., Gruppi A., Montes C.L., Acosta Rodríguez E.V. Interleukin-17 signaling influences CD8+ T cell immunity and tumor progression according to the IL-17 receptor subunit expression pattern in cancer cells. Oncoimmunology, 2023, Vol. 12, no. 1, 2261326. doi: 10.1080/2162402X.2023.2261326.Ru Y., Kechris K.J., Tabakoff B., Hoffman P., Radcliffe R.A., Bowler R., Mahaffey S, Rossi S, Calin G.A., Bemis L., Theodorescu D. The multiMiR R package and database: integration of microRNA-target interactions along with their disease and drug associations. Nucleic Acids Res., 2014, Vol. 42, no. 17, e133. doi: 10.1093/nar/gku631Ru Y., Kechris K.J., Tabakoff B., Hoffman P., Radcliffe R.A., Bowler R., Mahaffey S, Rossi S, Calin G.A., Bemis L., Theodorescu D. The multiMiR R package and database: integration of microRNA-target interactions along with their disease and drug associations. Nucleic Acids Res., 2014, Vol. 42, no. 17, e133. doi: 10.1093/nar/gku631Saeed H., Leibowitz B.J., Zhang L., Yu J. Targeting Myc-driven stress addiction in colorectal cancer. Drug Resist. Updat., 2023, Vol. 69, 100963. doi: 10.1016/j.drup.2023.100963.Saeed H., Leibowitz B.J., Zhang L., Yu J. Targeting Myc-driven stress addiction in colorectal cancer. Drug Resist. Updat., 2023, Vol. 69, 100963. doi: 10.1016/j.drup.2023.100963.Sawicki T., Ruszkowska M., Danielewicz A., Niedźwiedzka E., Arłu-kowicz T., Przybyłowicz K.E. A review of colorectal cancer in terms of epidemi-ology, risk factors, development, symptoms and diagnosis. Cancers (Basel), 2021, Vol. 13, no. 9, 2025. doi: 10.3390/cancers13092025.Sawicki T., Ruszkowska M., Danielewicz A., Niedźwiedzka E., Arłu-kowicz T., Przybyłowicz K.E. A review of colorectal cancer in terms of epidemi-ology, risk factors, development, symptoms and diagnosis. Cancers (Basel), 2021, Vol. 13, no. 9, 2025. doi: 10.3390/cancers13092025.Shah A.A., Kamal M.A., Akhtar S. Tumor Angiogenesis and VEGFR-2: Mechanism, pathways and current biological therapeutic interventions. Curr. Drug Metab., 2021, Vol. 22, no. 1, pp. 50-59.Shah A.A., Kamal M.A., Akhtar S. Tumor Angiogenesis and VEGFR-2: Mechanism, pathways and current biological therapeutic interventions. Curr. Drug Metab., 2021, Vol. 22, no. 1, pp. 50-59.Shannon P., Markiel A., Ozier O., Baliga N.S., Wang J.T., Ramage D., Amin N., Schwikowski B., Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, Vol. 13, no. 11, pp. 2498-2504.Shannon P., Markiel A., Ozier O., Baliga N.S., Wang J.T., Ramage D., Amin N., Schwikowski B., Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, Vol. 13, no. 11, pp. 2498-2504.Shimabukuro-Vornhagen A., Schlößer H.A., Gryschok L., Malcher J., Wennhold K., Garcia-Marquez M., Herbold T., Neuhaus L.S., Becker H.J., Fiedler A., Scherwitz P., Koslowsky T., Hake R., Stippel D.L., Hölscher A.H., Eidt S., Hallek M., Theurich S., von Bergwelt-Baildon M.S. Characterization of tumor-associated B-cell subsets in patients with colorectal cancer. Oncotarget, 2014, Vol. 5, no. 13, pp. 4651-4664.Shimabukuro-Vornhagen A., Schlößer H.A., Gryschok L., Malcher J., Wennhold K., Garcia-Marquez M., Herbold T., Neuhaus L.S., Becker H.J., Fiedler A., Scherwitz P., Koslowsky T., Hake R., Stippel D.L., Hölscher A.H., Eidt S., Hallek M., Theurich S., von Bergwelt-Baildon M.S. Characterization of tumor-associated B-cell subsets in patients with colorectal cancer. Oncotarget, 2014, Vol. 5, no. 13, pp. 4651-4664.Sorrentino C., D’Antonio L., Fieni C., Ciummo S.L., Di Carlo E. Colorectal cancer-associated immune exhaustion involves T and B lymphocytes and conventional NK cells and correlates with a shorter overall survival. Front. Immunol., 2021, Vol. 12, 778329. doi: 10.3389/fimmu.2021.778329.Sorrentino C., D’Antonio L., Fieni C., Ciummo S.L., Di Carlo E. Colorectal cancer-associated immune exhaustion involves T and B lymphocytes and conventional NK cells and correlates with a shorter overall survival. Front. Immunol., 2021, Vol. 12, 778329. doi: 10.3389/fimmu.2021.778329.Sui G., Qiu Y., Yu H., Kong Q., Zhen B. Interleukin-17 promotes the development of cisplatin resistance in colorectal cancer. Oncol. Lett., 2019, Vol. 17, no. 1, pp. 944-950.Sui G., Qiu Y., Yu H., Kong Q., Zhen B. Interleukin-17 promotes the development of cisplatin resistance in colorectal cancer. Oncol. Lett., 2019, Vol. 17, no. 1, pp. 944-950.Sun Z., Li G., Shang D., Zhang J., Ai L., Liu M. Identification of microsatellite instability and immunerelated prognostic biomarkers in colon adenocarcinoma. Front. Immunol., 2022, Vol. 13, 988303. doi: 10.3389/fimmu.2022.988303Sun Z., Li G., Shang D., Zhang J., Ai L., Liu M. Identification of microsatellite instability and immunerelated prognostic biomarkers in colon adenocarcinoma. Front. Immunol., 2022, Vol. 13, 988303. doi: 10.3389/fimmu.2022.988303Talaat I.M., Elemam N.M., Zaher S., Saber-Ayad M. Checkpoint molecules on infiltrating immune cells in colorectal tumor microenvironment. Front. Med. (Lausanne), 2022, Vol. 9, 955599. doi: 10.3389/fmed.2022.955599.Talaat I.M., Elemam N.M., Zaher S., Saber-Ayad M. Checkpoint molecules on infiltrating immune cells in colorectal tumor microenvironment. Front. Med. (Lausanne), 2022, Vol. 9, 955599. doi: 10.3389/fmed.2022.955599.Ulgen E., Ozisik O., Sezerman O.U. pathfindR: An R package for com-prehensive identification of enriched pathways in omics data through active subnetworks. Front. Genet., 2019, Vol. 10, 858. doi: 10.3389/fgene.2019.00858.Ulgen E., Ozisik O., Sezerman O.U. pathfindR: An R package for com-prehensive identification of enriched pathways in omics data through active subnetworks. Front. Genet., 2019, Vol. 10, 858. doi: 10.3389/fgene.2019.00858.Wang Z., Ao X., Shen Z., Ao L., Wu X., Pu C., Guo W., Xing W., He M., Yuan H., Yu J., Li L., Xu X. TNF-α augments CXCL10/CXCR3 axis activity to induce Epithelial-Mesenchymal Transition in colon cancer cell. Int. J. Biol. Sci., 2021, Vol. 17, no. 11, pp. 2683-2702.Wang Z., Ao X., Shen Z., Ao L., Wu X., Pu C., Guo W., Xing W., He M., Yuan H., Yu J., Li L., Xu X. TNF-α augments CXCL10/CXCR3 axis activity to induce Epithelial-Mesenchymal Transition in colon cancer cell. Int. J. Biol. Sci., 2021, Vol. 17, no. 11, pp. 2683-2702.Wu T., Yang W., Sun A., Wei Z., Lin Q. The Role of CXC chemokines in cancer progression. Cancers (Basel), 2022, Vol. 15, no. 1, 167. doi: 10.3390/cancers15010167Wu T., Yang W., Sun A., Wei Z., Lin Q. The Role of CXC chemokines in cancer progression. Cancers (Basel), 2022, Vol. 15, no. 1, 167. doi: 10.3390/cancers15010167Xiao Y, Freeman GJ. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov., 2015, Vol. 5, no. 1, pp. 16-18. doi: 10.1158/2159-8290.CD14-1397.Xiao Y, Freeman GJ. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov., 2015, Vol. 5, no. 1, pp. 16-18. doi: 10.1158/2159-8290.CD14-1397.Xie S., Cai Y., Chen D., Xiang Y., Cai W., Mao J., Ye J. Single-cell tran-scriptome analysis reveals heterogeneity and convergence of the tumor microenvi-ronment in colorectal cancer. Front. Immunol., 2023, Vol. 13, 1003419. doi: 10.3389/fimmu.2022.1003419.Xie S., Cai Y., Chen D., Xiang Y., Cai W., Mao J., Ye J. Single-cell tran-scriptome analysis reveals heterogeneity and convergence of the tumor microenvi-ronment in colorectal cancer. Front. Immunol., 2023, Vol. 13, 1003419. doi: 10.3389/fimmu.2022.1003419.Zeng K., Li W., Wang Y., Zhang Z., Zhang L., Zhang W., Xing Y., Zhou C. Inhibition of CDK1 overcomes oxaliplatin resistance by regulating ACSL4-mediated ferroptosis in colorectal cancer. Adv. Sci. (Weinh.), 2023, Vol. 10, no. 25, e2301088. doi: 10.1002/advs.202301088.Zeng K., Li W., Wang Y., Zhang Z., Zhang L., Zhang W., Xing Y., Zhou C. Inhibition of CDK1 overcomes oxaliplatin resistance by regulating ACSL4-mediated ferroptosis in colorectal cancer. Adv. Sci. (Weinh.), 2023, Vol. 10, no. 25, e2301088. doi: 10.1002/advs.202301088.Zhang P., Kawakami H., Liu W., Zeng X., Strebhardt K., Tao K., Huang S., Sinicrope F.A. Targeting CDK1 and MEK/ERK Overcomes Apoptotic Re-sistance in BRAF-mutant human colorectal cancer. Mol. Cancer Res., 2018, Vol. 16, no. 3, pp. 378-389.Zhang P., Kawakami H., Liu W., Zeng X., Strebhardt K., Tao K., Huang S., Sinicrope F.A. Targeting CDK1 and MEK/ERK Overcomes Apoptotic Re-sistance in BRAF-mutant human colorectal cancer. Mol. Cancer Res., 2018, Vol. 16, no. 3, pp. 378-389.Zhang J., Ji C., Li W., Mao Z., Shi Y., Shi H., Ji R., Qian H., Xu W., Zhang X. Tumor-educated neutrophils activate mesenchymal stem cells to promote gastric cancer growth and metastasis. Front. Cell Dev. Biol., 2020, Vol. 8, 788. doi: 10.3389/fcell.2020.00788.Zhang J., Ji C., Li W., Mao Z., Shi Y., Shi H., Ji R., Qian H., Xu W., Zhang X. Tumor-educated neutrophils activate mesenchymal stem cells to promote gastric cancer growth and metastasis. Front. Cell Dev. Biol., 2020, Vol. 8, 788. doi: 10.3389/fcell.2020.00788.Zhang X., Shi H., Yuan X., Jiang P., Qian H., Xu W. Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration. Mol. Cancer, 2018, Vol. 17, no. 1, 146. doi: 10.1186/s12943-018-0898-6.Zhang X., Shi H., Yuan X., Jiang P., Qian H., Xu W. Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration. Mol. Cancer, 2018, Vol. 17, no. 1, 146. doi: 10.1186/s12943-018-0898-6.Zhang Y., Zhao Y., Li Q., Wang Y. Macrophages, as a promising strategy to targeted treatment for colorectal cancer metastasis in tumor immune microenvironment. Front. Immunol., 2021, Vol. 12, 685978. doi: 10.3389/fimmu.2021.685978.Zhang Y., Zhao Y., Li Q., Wang Y. Macrophages, as a promising strategy to targeted treatment for colorectal cancer metastasis in tumor immune microenvironment. Front. Immunol., 2021, Vol. 12, 685978. doi: 10.3389/fimmu.2021.685978.Zheng Z., Wieder T., Mauerer B., Schäfer L., Kesselring R., Braumüller H. T cells in colorectal cancer: unravelling the function of different Т cell subsets in the tumor microenvironment. Int. J. Mol. Sci., 2023, Vol. 24, no. 14, 11673. doi: 10.3390/ijms241411673.Zheng Z., Wieder T., Mauerer B., Schäfer L., Kesselring R., Braumüller H. T cells in colorectal cancer: unravelling the function of different Т cell subsets in the tumor microenvironment. Int. J. Mol. Sci., 2023, Vol. 24, no. 14, 11673. doi: 10.3390/ijms241411673.Zheng W., Wu J., Peng Y., Sun J., Cheng P., Huang Q. Tumor-associated neutrophils in colorectal cancer development, progression and immunotherapy. Cancers (Basel), 2022, Vol. 14, no. 19, 4755. doi: 10.3390/cancers14194755.Zheng W., Wu J., Peng Y., Sun J., Cheng P., Huang Q. Tumor-associated neutrophils in colorectal cancer development, progression and immunotherapy. Cancers (Basel), 2022, Vol. 14, no. 19, 4755. doi: 10.3390/cancers14194755.Zhuo C., Ruan Q., Zhao X., Shen Y., Lin R. CXCL1 promotes colon cancer progression through activation of NF-κB/P300 signaling pathway. Biol. Direct, 2022, Vol. 17, no.1, pp. 34. doi: 10.1186/s13062-022-00348-4.Zhuo C., Ruan Q., Zhao X., Shen Y., Lin R. CXCL1 promotes colon cancer progression through activation of NF-κB/P300 signaling pathway. Biol. Direct, 2022, Vol. 17, no.1, pp. 34. doi: 10.1186/s13062-022-00348-4.

The authors declare that there are no conflicts of interest present.