Russian Journal of Biotherapy

Российский биотерапевтический журнал

1726-97841726-9792

Publishing House ABV Press

1133

10.17650/1726-9784-2018-17-4-106-110

ORIGINAL REPORTS

ОРИГИНАЛЬНЫЕ СТАТЬИ

Association of gastric cancer main signaling pathway gene expression with metastasis

Ассоциация экспрессии генов основных сигнальных путей развития рака желудка с его метастазированием.

https://orcid.org/0000-0003-4778-9726

Kipkeeva

F. M.

Кипкеева

Ф. М.

Russian Federation

1 Moskvorechie St., Moscow 115478

115478 Москва, ул. Москворечье, 1

Фатима Магомедовна Кипкеева

Foty_k@mail.ru

https://orcid.org/0000-0002-2345-2056

Muzaffarova

Т. А.

Музаффарова

Т. А.

Russian Federation

1 Moskvorechie St., Moscow 115478

115478 Москва, ул. Москворечье, 1

https://orcid.org/0000-0002-9608-4696

Nikulin

M. P.

Никулин

М. П.

Russian Federation

24 Kashirskoe shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0001-6576-5512

Apanovich

P. V.

Апанович

П. В.

Russian Federation

1 Moskvorechie St., Moscow 115478

115478 Москва, ул. Москворечье, 1

https://orcid.org/0000-0002-5403-2396

Nered

S. N.

Неред

С. Н.

Russian Federation

24 Kashirskoe shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0003-1806-8401

Narimanov

M. N.

Нариманов

М. Н.

Russian Federation

24 Kashirskoe shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

Malekhova

O. A.

Малихова

О. А.

Russian Federation

24 Kashirskoe shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-7673-4284

Bogush

Т. А.

Богуш

Т. А.

Russian Federation

24 Kashirskoe shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-5229-8203

Stilidi

I. S.

Стилиди

И. С.

Russian Federation

24 Kashirskoe shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-7001-9116

Karpukhin

A. V.

Карпухин

А. В.

Russian Federation

1 Moskvorechie St., Moscow 115478

115478 Москва, ул. Москворечье, 1

Research Centre for Medical GeneticsФГБНУ «Медико-генетический научный центр»

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава России

11122018

174

1061101101201911012019

2018

https://bioterapevt.abvpress.ru/jour/article/view/1133

Objective of the study. Identification of genes, the expression of which is associated with the metastasis of gastric cancer tumor.

Materials and methods. Quantitative real-time PCR on paired tumor – normal samples.

Results. An association with the metastasis of the VEGFR1, FGFR2 and NRP-1 gene expression is shown. The odds ratio (OR) was the highest for the FGFR2 gene: OR 175.00; 95 % CI 8.972–3413.271; for the VEGFR1 gene, OR 4.622, 95 % CI 1.240–17.227, for NRP1 – OR 2.667; 95 % CI 0.597–11.915. When assessing the jointly elevated expression of VEGFR1 and NRP1 genes, OR 5,778; 95 % CI 1.393–23.909; p = 0.0147. The frequency of increased expression of FGFR2 was 5 % in case of metastasis, while in the case of localized GC it reached 53 %.

Conclusion. The target drug against FGFR2, which is being developed, is likely to have a limited 5–10 % frequency of effective action in metastatic GC. Its use in the early stages of GC can help prevent the transition of the tumor to the metastatic stage. The possible interact tion of VEGFR1 and NRP1 will result in a small contribution to the metastasis of GC as compared to the effect of VEGFR1-only expression.

Цель исследования – выявление генов, экспрессия которых ассоциирована с метастазированием опухоли рака желудка (РЖ).

Материалы и методы. Использовали метод количественной полимеразной цепной реакции в реальном времени на парных образцах опухоль – норма.

Результаты. Показана ассоциация с метастазированием экспрессии генов VEGF R1, FGFR2 и NRP-1. Значение отношения шансов (ОШ) оказалось наибольшим для гена FGFR2: ОШ 175,00; 95 % доверительный интервал (ДИ) 8,972–3413,271; для гена VEGFR1 – ОШ 4,622; 95 % ДИ 1,240–17,227, для NRP1 – ОШ 2,667; 95 % ДИ 0,597–11,915. При оценке совместно повышенной экспрессии генов VEGFR1 и NRP1 – ОШ 5,778; 95 % ДИ 1,393–23,909; р = 0,0147. Частота повышенной экспрессии FGFR2 составила 5 % при диссеминированном РЖ, в то время как при локализованном РЖ она достигает 53 %.

Заключение. Разрабатываемый таргетный препарат против FGFR2, скорее всего, при диссеминированном РЖ будет иметь ограниченную 5–10 % частоту эффективного действия. Его применение на ранних стадиях РЖ может способствовать предотвращению перехода опухоли в метастатическую стадию. Возможное взаимодействие VEGFR1 и NRP1 будет приводить к небольшому вкладу в метастазирование РЖ по сравнению с влиянием экспрессии только VEGFR1.

gastric cancermetastasisgene expression

рак желудкаметастазированиеэкспрессия генов

1. Sitarz R., Skierucha M., Mielko J. Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res 2018;10:239–48. PMID: 29445300. DOI: 10.2147/CMAR.S149619.

Sitarz R., Skierucha M., Mielko J. Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res 2018;10:239–48. PMID: 29445300. DOI: 10.2147/CMAR.S149619.

2. Smyth E.C., Cunningham D. Targeted therapy for gastric cancer. Curr Treat Options Oncol 2012;13(3):377–89. DOI: 10.1007/s11864-012-0192-6.

Smyth E.C., Cunningham D. Targeted therapy for gastric cancer. Curr Treat Options Oncol 2012;13(3):377–89. DOI: 10.1007/s11864-012-0192-6.

3. Prud’homme G. J. and Glinka Y. Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity. Oncotarget 2012;3(9):921–39.

Prud’homme G. J. and Glinka Y. Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity. Oncotarget 2012;3(9):921–39.

4. Li L., Jiang X., Zhang Q. et al. Neuropilin-1 is associated with clinicopathology of gastric cancer and contributes to cell proliferation and migration as multifunctional coreceptors. J Experimental & Clinical Cancer Research 2016;35:16. PMID: 26795388. DOI: 10.1186/s13046-016-0291-5.

Li L., Jiang X., Zhang Q. et al. Neuropilin-1 is associated with clinicopathology of gastric cancer and contributes to cell proliferation and migration as multifunctional coreceptors. J Experimental & Clinical Cancer Research 2016;35:16. PMID: 26795388. DOI: 10.1186/s13046-016-0291-5.

5. Su X., Zhan P., Gavine P.R. et al. FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br J Cancer 2014;110(4):967–75. PMID: 24457912. DOI: 10.1038/bjc.2013.802.

Su X., Zhan P., Gavine P.R. et al. FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br J Cancer 2014;110(4):967–75. PMID: 24457912. DOI: 10.1038/bjc.2013.802.

6. Liang Xie, Xinying Su, Lin Zhang et al. FGFR2 Gene Amplification in Gastric Cancer Predicts Sensitivity to the Selective FGFR Inhibitor AZD4547 2572. Clin Cancer Res 2013;19:2572–83. PMID: 23493349. DOI: 10.1158/1078-0432.CCR-12-3898.

Liang Xie, Xinying Su, Lin Zhang et al. FGFR2 Gene Amplification in Gastric Cancer Predicts Sensitivity to the Selective FGFR Inhibitor AZD4547 2572. Clin Cancer Res 2013;19:2572–83. PMID: 23493349. DOI: 10.1158/1078-0432.CCR-12-3898.

7. Murase H., Inokuchi M., Takagi Y. et al. Prognostic significance of the co-overexpression of fibroblast growth factor receptors 1, 2 and 4 in gastric cancer. Mol Clin Oncol 2014;2(4):509–17. PMID: 24940486. DOI: 10.3892/mco.2014.293.

Murase H., Inokuchi M., Takagi Y. et al. Prognostic significance of the co-overexpression of fibroblast growth factor receptors 1, 2 and 4 in gastric cancer. Mol Clin Oncol 2014;2(4):509–17. PMID: 24940486. DOI: 10.3892/mco.2014.293.

8. Shoji H., Yamada Y., Okita N. et al. Amplification of FGFR2 Gene in Patients with Advanced Gastric Cancer Receiving Chemotherapy: Prevalence and Prognostic Significance. Anticancer Res 2015;35(9):5055–61. PMID: 26254407.

Shoji H., Yamada Y., Okita N. et al. Amplification of FGFR2 Gene in Patients with Advanced Gastric Cancer Receiving Chemotherapy: Prevalence and Prognostic Significance. Anticancer Res 2015;35(9):5055–61. PMID: 26254407.

9. Dang Y-Z., Zhang Y., Li J-P. et al. High VEGFR1/2 expression levels are predictors of poor survival in patients with cervical cancer. Medicine (Baltimore) 2017;96(1):e5772. PMID: 28072723. DOI: 10.1097/MD.0000000000005772.

Dang Y-Z., Zhang Y., Li J-P. et al. High VEGFR1/2 expression levels are predictors of poor survival in patients with cervical cancer. Medicine (Baltimore) 2017;96(1):e5772. PMID: 28072723. DOI: 10.1097/MD.0000000000005772.

10.

10. Тырсина Е.Г., Никулицкий С.И., Иншаков А.Н., Рябая О.О. VEGF-R1 как потенциальная молекулярная мишень противоопухолевой терапии. Доклады академии наук 2018;478(2):236–39. DOI: 10.7868/S086956521802024X. [Tyrsina E.G., Nikulickij S.I., Inshakov A.N., Ryabaya O.O. VEGFR1 as a potential molecular target of anticancer therapy. Dokladj akademii nauk = Reports of the Academy of Sciences 2018;478(2):236–39. (In Russ.)].

Тырсина Е.Г., Никулицкий С.И., Иншаков А.Н., Рябая О.О. VEGF-R1 как потенциальная молекулярная мишень противоопухолевой терапии. Доклады академии наук 2018;478(2):236–39. DOI: 10.7868/S086956521802024X. [Tyrsina E.G., Nikulickij S.I., Inshakov A.N., Ryabaya O.O. VEGFR1 as a potential molecular target of anticancer therapy. Dokladj akademii nauk = Reports of the Academy of Sciences 2018;478(2):236–39. (In Russ.)].

11.

11. Mehnert J.M., McCarthy M. M., Aziz S.A. et al. VEGF, VEGFR1, and VEGFR2 expression in melanoma. Journal of Clinical Oncology 2007;25 (18, suppl):8520. DOI: 10.1200/jco.2007.25.18_suppl.8520.

Mehnert J.M., McCarthy M. M., Aziz S.A. et al. VEGF, VEGFR1, and VEGFR2 expression in melanoma. Journal of Clinical Oncology 2007;25 (18, suppl):8520. DOI: 10.1200/jco.2007.25.18_suppl.8520.

12.

12. Jayasinghe C., Simiantonaki N., Kirkpatrick C.J. Cell type- and tumor zone-specific expression of pVEGFR-1 and its ligands influence colon cancer metastasis. BMC Cancer 2015;15:104. PMID: 25880726. DOI: 10.1186/s12885-015-1130-3.

Jayasinghe C., Simiantonaki N., Kirkpatrick C.J. Cell type- and tumor zone-specific expression of pVEGFR-1 and its ligands influence colon cancer metastasis. BMC Cancer 2015;15:104. PMID: 25880726. DOI: 10.1186/s12885-015-1130-3.

13.

13. Weddell J.C., Chen S., Imoukhuede P.I. VEGFR1 promotes cell migration and proliferation through PLCγ and PI3K pathways. NPJ Systems Biology and Applications 2018;4:1. PMID: 29263797. DOI: 10.1038/s41540-017-0037-9.

Weddell J.C., Chen S., Imoukhuede P.I. VEGFR1 promotes cell migration and proliferation through PLCγ and PI3K pathways. NPJ Systems Biology and Applications 2018;4:1. PMID: 29263797. DOI: 10.1038/s41540-017-0037-9.

14.

14. Tse B.W. C., Volpert M., Ratther E. et al. Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality. Oncogene 2017;36(24):3417–27. PMID: 28092670. DOI: 10.1038/onc.2016.482.

Tse B.W. C., Volpert M., Ratther E. et al. Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality. Oncogene 2017;36(24):3417–27. PMID: 28092670. DOI: 10.1038/onc.2016.482.