PROLIFERATION AND APOPTOSIS OF B-CELL LYMPHOMA CELLS UNDER TARGETED REGULATION OF FOXO3 BY miR-155 miR-155, FOXO3, B-cell lymphoma, proliferation, apoptosis, clinical characteristics

Main Article Content

Xiaoqiang Zheng
Hongbing Rui
Ying Liu
Jinfeng Dong

Keywords

miR-155, FOXO3, B-cell lymphoma, proliferation, apoptosis, clinical characteristics

Abstract

This study aimed to explore the proliferation and apoptosis of B-cell lymphoma cells under targeted regulation of FOXO3 by miR-155. We analyzed the differences between B-cell lymphoma cells and B lymphocytes in expressions of miR-155 and FOXO3, explored the effects of miR-155 on proliferation and apoptosis of B-cell lymphoma cells, and relevant mechanisms, and also analyzed the relationship between expressions of miR-155 and FOXO3 in 42 patients with diffuse large B-cell lymphoma (DLBCL) and clinical characteristics of them. B-cell lymphoma cells showed a higher expression of miR-155 and a low expression of FOXO3 than B lymphocytes (both P<0.05). B-cell lymphoma cells transfected with miR-155-inhibitor showed significantly decreased expression of miR-155, significantly weakened cell proliferation ability and increased cell apoptosis rate (all P<0.05), and they also showed up-regulated expression of FOXO3 (P<0.05). Dual luciferase reporter assay revealed that there were targeted binding sites between miR-155 and FOXO3. Compared with B-cell lymphoma cells transfected with miR-155-inhibitor alone, those with co-transfection showed lower expression of FOXO3, higher proliferation and lower cell apoptosis rate (all P<0.05). The expression of miR-155 in DLBCL tissues was higher than that in tumor-adjacent tissues (P<0.05), and the expressions of miR-155 and FOXO3 were closely related to the international prognostic index (IPI) and the 5-year prognosis and survival of the patients (P<0.05). miR-155 can promote the proliferation of B-cell lymphoma cells and suppress apoptosis of them by targeted inhibiting FOXO3, and both over-expression of miR-155 and low expression of FOXO3 are related to poor prognosis of DLBCL patients.

Downloads

Download data is not yet available.
Abstract 186 | PDF Downloads 19 HTML Downloads 23

References

1. Ren W, Ye X, Su H, Li W, Liu D, Pirmoradian M, Wang X, Zhang B, Zhang Q, Chen L, et al: Genetic landscape of hepatitis B virus–associated diffuse large B-cell lymphoma. Blood 131: 2670-2681, 2018.
2. Swerdlow SH: WHO classification of tumours of haematopoietic and lymphoid tissues. WHO classification of tumours 22008: 439, 2008.
3. Horwitz SM, Zelenetz AD, Gordon LI, Wierda WG, Abramson JS, Advani RH, Andreadis CB, Bartlett N, Byrd JC, Fayad LE, et al: NCCN guidelines insights:non-Hodgkin's lymphomas, version 3.2016. J Natl Compr Canc Netw 14: 1067-1079, 2016.
4. Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE, Carty S, Lam LT, Shaffer AL, Xiao W, et al: Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A 105: 13520-13525, 2008.
5. Gonçalves OSL, Wheeler G, Dalmay T, et al: Detection of miRNA cancer biomarkers using light activated Molecular Beacons. Rsc Advances 9: 12766-12783, 2019.
6. Mullany LE, Herrick JS, Sakoda LC, Samowitz W, Stevens JR, Wolff RK and Slattery ML: miRNA involvement in cell cycle regulation in colorectal cancer cases. Genes Cancer 9: 53, 2018.
7. Zhang J, Wei B, Hu H, Liu F, Tu Y, Zhao M and Wu D: Preliminary study on decreasing the expression of FOXP3 with miR-155 to inhibit diffuse large B-cell lymphoma. Oncol Lett 14: 1711-1718, 2017.
8. Huang X, Shen Y, Liu M, Bi C, Jiang C, Iqbal J, McKeithan TW, Chan WC, Ding SJ, Fu K: Quantitative proteomics reveals that miR-155 regulates the PI3K-AKT pathway in diffuse large B-cell lymphoma. Am J Pathol 181: 26-33, 2012.
9. Coomans de Brachène A and Demoulin JB: FOXO transcription factors in cancer development and therapy. Cell Mol Life Sci 73: 1159-1172, 2016.
10. Obrador-Hevia A, Serra-Sitjar M, Rodríguez J, Villalonga P and Fernández de Mattos S: The tumour suppressor FOXO3 is a key regulator of mantle cell lymphoma proliferation and survival. Br J Haematol 156: 334-345, 2012.
11. He B, Yan F and Wu C: Overexpressed miR-195 attenuated immune escape of diffuse large B-cell lymphoma by targeting PD-L1. Biomed Pharmacother 98: 95-101, 2018.
12. Huang J, Jiao J, Xu W, Zhao H, Zhang C, Shi Y and Xiao Z: MiR-155 is upregulated in patients with active tuberculosis and inhibits apoptosis of monocytes by targeting FOXO3. Mol Med Rep 12: 7102-7108, 2015.
13. Ling N, Gu J, Lei Z, Li M, Zhao J, Zhang HT and Li X: microRNA-155 regulates cell proliferation and invasion by targeting FOXO3a in glioma. Oncol Rep 30: 2111-2118, 2013.
14. Van Roosbroeck K, Fanini F, Setoyama T, Ivan C, Rodriguez-Aguayo C, Fuentes-Mattei E, Xiao L, Vannini I, Redis RS, D'Abundo L, et al: Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. Clin Cancer Res 23: 2891-2904, 2017.
15. Zargar S, Tomar V, Shyamsundar V, Vijayalakshmi R, Somasundaram K and Karunagaran D: A feedback loop between microRNA 155 (miR-155), programmed cell death 4, and activation protein 1 modulates the expression of miR-155 and tumorigenesis in tongue cancer. Mol?Cell?Biol 39: e00410-18, 2019.
16. Yao S, Fan LY and Lam EW: The FOXO3-FOXM1 axis:A key cancer drug target and a modulator of cancer drug resistance[C]//Seminars in cancer biology. Semin Cancer Biol 50: 77-89, 2018.
17. Kumazoe M, Takai M, Bae J, Hiroi S, Huang Y, Takamatsu K, Won Y, Yamashita M, Hidaka S, Yamashita S, et al: FOXO3 is essential for CD44 expression in pancreatic cancer cells. Oncogene 36: 2643, 2017.
18. Slezak-Prochazka I, Kluiver J, de Jong D, Smigielska-Czepiel K, Kortman G, Winkle M, Rutgers B, Koerts J, Visser L, Diepstra A, et al: Inhibition of the miR-155 target NIAM phenocopies the growth promoting effect of miR-155 in B-cell lymphoma. Oncotarget 7: 2391, 2016.
19. Ushmorov A and Wirth T: FOXO in B-cell lymphopoiesis and B cell neoplasia[C]//Seminars in cancer biology. Semin Cancer Biol 50: 132-141, 2018.
20. Zhang L, Cai M, Gong Z, Zhang B, Li Y, Guan L, Hou X, Li Q, Liu G, Xue Z, et al: Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis. J Clin Invest 127: 2159-2175, 2017.
21. Kumazoe M, Takai M, Hiroi S, Takeuchi C, Kadomatsu M, Nojiri T, Onda H, Bae J, Huang Y, Takamats u K, et al: The FOXO3/PGC-1? signaling axis is essential for cancer stem cell properties of pancreatic ductal adenocarcinoma. J Biol Chem 292: 10813-10823, 2017.
22. Kim S, Lee E, Jung J, Lee JW, Kim HJ, Kim J, Yoo HJ, Lee HJ, Chae SY, Jeon SM, et al: microRNA-155 positively regulates glucose metabolism via PIK3R1-FOXO3a-cMYC axis in breast cancer. Oncogene 37: 2982, 2018.
23. Zhang Y, Zhao H and Zhang L: Identification of the tumor suppressive function of circular RNA FOXO3 in non small cell lung cancer through sponging miR 155. Mol Med Rep 17: 7692-7700, 2018.
24. Ji H, Tian D, Zhang B, Zhang Y, Yan D and Wu S: Overexpression of miR 155 in clear cell renal cell carcinoma and its oncogenic effect through targeting FOXO3a. Exp Ther Med 13: 2286-2292, 2017.
25. Andor N, Simonds EF, Czerwinski DK, Chen J, Grimes SM, Wood-Bouwens C, Zheng GXY, Kubit MA, Greer S, Weiss WA, et al: Single-cell RNA-Seq of follicular lymphoma reveals malignant B-cell types and coexpression of T-cell immune checkpoints. Blood 133: 1119-1129, 2019.
26. Togher S, Larange A, Schoenberger SP and Feau S:FoxO3 is a negative regulator of primary CD8+ T?cell expansion but not of memory formation. Immunol Cell Biol 93: 120-125, 2015.
27. Ottens K, Hinman RM, Barrios E, Skaug?B, Davis LS, Li QZ, Castrillon DH and Satterthwaite AB: Foxo3 Promotes Apoptosis of B Cell Receptor–Stimulated Immature B Cells, Thus Limiting the Window for Receptor Editing. J Immunol 201: 940-949, 2018.
28. Due H, Svendsen P, Bødker JS, Schmitz A, Bøgsted M, Johnsen HE, El-Galaly TC, Roug AS and Dybkær K: miR-155 as a Biomarker in B-Cell Malignancies. Biomed Res Int 2016: 1-14, 2016.
29. Ahmadvand M, Eskandari M, Pashaiefar H, Yaghmaie M, Manoochehrabadi S, Khakpour G, Sheikhsaran F and Montazer Zohour M: Over expression of circulating miR-155 predicts prognosis in diffuse large B-cell lymphoma. Leuk Res 70: 45-48, 2018.
30. Khoshinani HM, Afshar S, Pashaki AS, Mahdavinezhad A, Nikzad S, Najafi R, Amini R, Gholami MH, Khoshghadam A and Saidijam M: Involvement of miR-155/FOXO3a and miR-222/PTEN in acquired radioresistance of colorectal cancer cell line. Jpn J Radiol 35: 664-672, 2017.