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Current Radiopharmaceuticals

Editor-in-Chief

ISSN (Print): 1874-4710
ISSN (Online): 1874-4729

Research Article

Gamma Knife Radiosurgery Modulates micro-RNA Levels in Patients with Brain Metastasis

Author(s): Imran Khan, Kerime Akdur, Sadaf Mahfooz, Elif Burce Elbasan, Ayten Sakarcan, Busra Karacam, Georges Sinclair, Sahabettin Selek, Fahri Akbas and Mustafa Aziz Hatiboglu*

Volume 16, Issue 3, 2023

Published on: 15 February, 2023

Page: [204 - 213] Pages: 10

DOI: 10.2174/1874471016666230202164557

Price: $65

Abstract

Background: The relation between micro-RNA (miRNA) modulation and immune cell activity in high-dose radiation settings is not clearly understood.

Objective: To investigate the role of stereotactic radiosurgery (SRS) in (i) the regulation of tumorsuppressor and oncogenic miRNAs as well as (ii) its effect on specific immune cell subsets in patients with metastatic brain tumors (MBT).

Methods: 9 MBT patients who underwent gamma knife-based stereotactic radiosurgery (GKRS) and 8 healthy individuals were included. Serum samples were isolated at three-time intervals (before GKRS, 1 hour, and 1-month post-GKRS). Expressions of tumor-suppressor (miR-124) and oncogenic (miR-21, miR-181a, miR-23a, miR-125b, and miR-17) miRNAs were quantified by qPCR. The lymphocytic frequency (CD3+, CD4+, CD8+, CD56+, CD19+, and CD16+) was investigated by means of flow cytometry.

Results: The median age was 64 years (range: 50-73 years). The median prescription dose was 20Gy (range: 16Gy-24Gy), all delivered in a single fraction. The median overall survival and progression- free survival were 7.8 months (range: 1.7-14.9 months) and 6.7 months (range: 1.1-11.5 months), respectively. Compared to healthy controls, baseline levels of oncogenic miRNAs were significantly higher, while tumor-suppressing miRNA levels remained markedly lower in MBT patients prior to GKRS. Following GKRS, there was a reduction in the expression of miR-21, miR-17, and miR-181a; simultaneously, increased expression increased of miR-124 was observed. No significant difference in immune cell subsets was noted post GKRSIn a similar fashion. We noted no correlation between patient characteristics, radiosurgery data, miRNA expression, and immune cell frequency.

Conclusion: For this specific population with MBT disease, our data suggest that stereotactic radiosurgery may modulate the expression of circulating tumor-suppressor and oncogenic miRNAs, ultimately enhancing key anti-tumoral responses. Further evaluation with larger cohorts is warranted.

Graphical Abstract

[1]
Soffietti, R. Rudā R.; Mutani, R. Management of brain metastases. J. Neurol., 2002, 249(10), 1357-1369.
[http://dx.doi.org/10.1007/s00415-002-0870-6] [PMID: 12382150]
[2]
Lin, X.; DeAngelis, L.M. Treatment of brain metastases. J. Clin. Oncol., 2015, 33(30), 3475-3484.
[http://dx.doi.org/10.1200/JCO.2015.60.9503] [PMID: 26282648]
[3]
Hatiboglu, M.A.; Akdur, K.; Sawaya, R. Neurosurgical management of patients with brain metastasis. Neurosurg. Rev., 2020, 43(2), 483-495.
[http://dx.doi.org/10.1007/s10143-018-1013-6] [PMID: 30058049]
[4]
Hatiboglu, M.A.; Tuzgen, S.; Akdur, K.; Chang, E.L. Treatment of high numbers of brain metastases with Gamma Knife radiosurgery: A review. Acta Neurochir., 2016, 158(4), 625-634.
[http://dx.doi.org/10.1007/s00701-016-2707-6] [PMID: 26811300]
[5]
Dagoglu, N.; Karaman, S.; Caglar, H.B.; Oral, E.N. Abscopal effect of radiotherapy in the immunotherapy era: Systematic review of reported cases. Cureus, 2019, 11(2), e4103.
[http://dx.doi.org/10.7759/cureus.4103] [PMID: 31057997]
[6]
Liu, X.; Liu, Z.; Wang, D.; Han, Y.; Hu, S.; Xie, Y.; Liu, Y.; Zhu, M.; Guan, H.; Gu, Y.; Zhou, P.K. Effects of low dose radiation on immune cells subsets and cytokines in mice. Toxicol. Res., 2020, 9(3), 249-262.
[http://dx.doi.org/10.1093/toxres/tfaa017] [PMID: 32670556]
[7]
Lumniczky, K.; Candéias, S.M.; Gaipl, U.S.; Frey, B. Editorial: Radiation and the immune system: Current knowledge and future perspectives. Front. Immunol., 2018, 8, 1933.
[http://dx.doi.org/10.3389/fimmu.2017.01933] [PMID: 29410662]
[8]
Lewis, B.P.; Burge, C.B.; Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell, 2005, 120(1), 15-20.
[http://dx.doi.org/10.1016/j.cell.2004.12.035] [PMID: 15652477]
[9]
Petrescu, G.E.D.; Sabo, A.A.; Torsin, L.I.; Calin, G.A.; Dragomir, M.P. MicroRNA based theranostics for brain cancer: Basic principles. J. Exp. Clin. Cancer Res., 2019, 38(1), 231.
[http://dx.doi.org/10.1186/s13046-019-1180-5] [PMID: 31142339]
[10]
Liu, X.; Peng, H.; Liao, W.; Luo, A.; Cai, M.; He, J.; Zhang, X.; Luo, Z.; Jiang, H.; Xu, L. MiR-181a/b induce the growth, invasion, and metastasis of neuroblastoma cells through targeting ABI1. Mol. Carcinog., 2018, 57(9), 1237-1250.
[http://dx.doi.org/10.1002/mc.22839] [PMID: 29802737]
[11]
Yang, P.; Bu, P.; Li, C. miR-124 inhibits proliferation, migration and invasion of malignant melanoma cells via targeting versican. Exp. Ther. Med., 2017, 14(4), 3555-3562.
[http://dx.doi.org/10.3892/etm.2017.4998] [PMID: 29042947]
[12]
Hatiboglu, M.A.; Akdur, K. Evaluating critical brain radiation doses in the treatment of multiple brain lesions with gamma knife radiosurgery. Stereotact. Funct. Neurosurg., 2017, 95(4), 268-278.
[http://dx.doi.org/10.1159/000478272] [PMID: 28810243]
[13]
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method. Methods, 2001, 25(4), 402-408.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[14]
Scorsetti, M.; Navarria, P.; Ascolese, A.; Clerici, E.; Mancosu, P.; Picozzi, P.; Pecchioli, G.; Franzese, C.; Reggiori, G.; Tomatis, S. OS03.4 Gammaknife versus Linac based (EDGE) radiosurgery (SRS) for patients with limited brain metastases (BMS) from different solid tumor: A phase III randomized trial. Neuro-oncol., 2017, 19(S3), iii5-iii6.
[http://dx.doi.org/10.1093/neuonc/nox036.017]
[15]
Hatiboglu, M.A.; Kocyigit, A.; Guler, E.M.; Nalli, A.; Akdur, K.; Sakarcan, A. Gamma knife radiosurgery compared to whole brain radiation therapy enhances immunity via immunoregulatory molecules in patients with metastatic brain tumours. Br. J. Neurosurg., 2019, 34(6), 604-610.
[http://dx.doi.org/10.1080/02688697.2019.1642445] [PMID: 31317782]
[16]
Wang, Z.; Ji, F. Downregulation of microRNA-17-5p inhibits drug resistance of gastric cancer cells partially through targeting p21. Oncol. Lett., 2018, 15(4), 4585-4591.
[http://dx.doi.org/10.3892/ol.2018.7822] [PMID: 29541229]
[17]
Chistiakov, D.A.; Chekhonin, V.P. Contribution of microRNAs to radio- and chemoresistance of brain tumors and their therapeutic potential. Eur. J. Pharmacol., 2012, 684(1-3), 8-18.
[http://dx.doi.org/10.1016/j.ejphar.2012.03.031] [PMID: 22484336]
[18]
Zhao, J.; Fu, W.; Liao, H.; Dai, L.; Jiang, Z.; Pan, Y.; Huang, H.; Mo, Y.; Li, S.; Yang, G.; Yin, J. The regulatory and predictive functions of miR-17 and miR-92 families on cisplatin resistance of non-small cell lung cancer. BMC Cancer, 2015, 15(1), 731.
[http://dx.doi.org/10.1186/s12885-015-1713-z] [PMID: 26482648]
[19]
Chatterjee, A.; Chattopadhyay, D.; Chakrabarti, G. miR-17-5p downregulation contributes to paclitaxel resistance of lung cancer cells through altering beclin1 expression. PLoS One, 2014, 9(4), e95716.
[http://dx.doi.org/10.1371/journal.pone.0095716] [PMID: 24755562]
[20]
Dong, Z.; Ren, L.; Lin, L.; Li, J.; Huang, Y.; Li, J. Effect of microRNA-21 on multidrug resistance reversal in A549/DDP human lung cancer cells. Mol. Med. Rep., 2015, 11(1), 682-690.
[http://dx.doi.org/10.3892/mmr.2014.2662] [PMID: 25323306]
[21]
Najjary, S.; Mohammadzadeh, R.; Mokhtarzadeh, A.; Mohammadi, A.; Kojabad, A.B.; Baradaran, B. Role of miR-21 as an authentic oncogene in mediating drug resistance in breast cancer. Gene, 2020, 738, 144453.
[http://dx.doi.org/10.1016/j.gene.2020.144453] [PMID: 32035242]
[22]
Ping, W.; Gao, Y.; Fan, X.; Li, W.; Deng, Y.; Fu, X. MiR-181a contributes gefitinib resistance in non-small cell lung cancer cells by targeting GAS7. Biochem. Biophys. Res. Commun., 2018, 495(4), 2482-2489.
[http://dx.doi.org/10.1016/j.bbrc.2017.12.096] [PMID: 29269300]
[23]
Wang, H.; Tan, G.; Dong, L.; Cheng, L.; Li, K.; Wang, Z.; Luo, H. Circulating MiR-125b as a marker predicting chemoresistance in breast cancer. PLoS One, 2012, 7(4), e34210.
[http://dx.doi.org/10.1371/journal.pone.0034210] [PMID: 22523546]
[24]
Teplyuk, N.M.; Mollenhauer, B.; Gabriely, G.; Giese, A.; Kim, E.; Smolsky, M.; Kim, R.Y.; Saria, M.G.; Pastorino, S.; Kesari, S.; Krichevsky, A.M. MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. Neuro-oncol., 2012, 14(6), 689-700.
[http://dx.doi.org/10.1093/neuonc/nos074] [PMID: 22492962]
[25]
Lu, S.; Wang, S.; Geng, S.; Ma, S.; Liang, Z.; Jiao, B. Increased expression of microRNA-17 predicts poor prognosis in human glioma. J. biotechnol. Biomed., 2012, 2012, 970761.
[http://dx.doi.org/10.1155/2012/970761] [PMID: 23226946]
[26]
Hu, X.; Chen, D.; Cui, Y.; Li, Z.; Huang, J. Targeting microRNA-23a to inhibit glioma cell invasion via HOXD10. Sci. Rep., 2013, 3(1), 3423.
[http://dx.doi.org/10.1038/srep03423] [PMID: 24305689]
[27]
Wu, N.; Lin, X.; Zhao, X.; Zheng, L.; Xiao, L.; Liu, J.; Ge, L.; Cao, S. MiR-125b acts as an oncogene in glioblastoma cells and inhibits cell apoptosis through p53 and p38MAPK-independent pathways. Br. J. Cancer, 2013, 109(11), 2853-2863.
[http://dx.doi.org/10.1038/bjc.2013.672] [PMID: 24169356]
[28]
Banzhaf-Strathmann, J.; Edbauer, D. Good guy or bad guy: The opposing roles of microRNA 125b in cancer. Cell Commun. Signal., 2014, 12(1), 30.
[http://dx.doi.org/10.1186/1478-811X-12-30] [PMID: 24774301]
[29]
Toraih, E.A.; El-Wazir, A.; Abdallah, H.Y.; Tantawy, M.A.; Fawzy, M.S. Deregulated MicroRNA signature following glioblastoma irradiation. Cancer Contr., 2019, 26(1)
[http://dx.doi.org/10.1177/1073274819847226] [PMID: 31046428]
[30]
Qiao, W.; Guo, B.; Zhou, H.; Xu, W.; Chen, Y.; Liang, Y.; Dong, B. miR-124 suppresses glioblastoma growth and potentiates chemosensitivity by inhibiting AURKA. Biochem. Biophys. Res. Commun., 2017, 486(1), 43-48.
[http://dx.doi.org/10.1016/j.bbrc.2017.02.120] [PMID: 28242198]
[31]
Zhang, Y.; Zheng, L.; Lin, S.; Liu, Y.; Wang, Y.; Gao, F. MiR-124 enhances cell radiosensitivity by targeting PDCD6 in nasopharyngeal carcinoma. Int. J. Clin. Exp. Pathol., 2017, 10(12), 11461-11470.
[PMID: 31966501]
[32]
Demaria, S.; Formenti, S.C. Sensors of ionizing radiation effects on the immunological microenvironment of cancer. Int. J. Radiat. Biol., 2007, 83(11-12), 819-825.
[http://dx.doi.org/10.1080/09553000701481816] [PMID: 17852561]
[33]
Formenti, S.C.; Demaria, S. Combining radiotherapy and cancer immunotherapy: A paradigm shift. J. Natl. Cancer Inst., 2013, 105(4), 256-265.
[http://dx.doi.org/10.1093/jnci/djs629] [PMID: 23291374]
[34]
D’Souza, N.M.; Fang, P.; Logan, J.; Yang, J.; Jiang, W.; Li, J. Combining radiation therapy with immune checkpoint blockade for central nervous system malignancies. Front. Oncol., 2016, 6, 212.
[http://dx.doi.org/10.3389/fonc.2016.00212] [PMID: 27774435]
[35]
Takeshima, T.; Chamoto, K.; Wakita, D.; Ohkuri, T.; Togashi, Y.; Shirato, H.; Kitamura, H.; Nishimura, T. Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with Th1 cell therapy. Cancer Res., 2010, 70(7), 2697-2706.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-2982] [PMID: 20215523]
[36]
Kang, J.; Demaria, S.; Formenti, S. Current clinical trials testing the combination of immunotherapy with radiotherapy. J. Immunother. Cancer, 2016, 4(1), 51.
[http://dx.doi.org/10.1186/s40425-016-0156-7] [PMID: 27660705]
[37]
Dewan, M.Z.; Galloway, A.E.; Kawashima, N.; Dewyngaert, J.K.; Babb, J.S.; Formenti, S.C.; Demaria, S. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res., 2009, 15(17), 5379-5388.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-0265] [PMID: 19706802]
[38]
Shibamoto, Y.; Miyakawa, A.; Otsuka, S.; Iwata, H. Radiobiology of hypofractionated stereotactic radiotherapy: What are the optimal fractionation schedules? J. Radiat. Res., 2016, 57(S1), i76-i82.
[http://dx.doi.org/10.1093/jrr/rrw015] [PMID: 27006380]
[39]
Shibamoto, Y.; Otsuka, S.; Iwata, H.; Sugie, C.; Ogino, H.; Tomita, N. Radiobiological evaluation of the radiation dose as used in high-precision radiotherapy: effect of prolonged delivery time and applicability of the linear-quadratic model. J. Radiat. Res., 2012, 53(1), 1-9.
[http://dx.doi.org/10.1269/jrr.11095] [PMID: 21997195]
[40]
Najafi, M.; Motevaseli, E.; Shirazi, A.; Geraily, G.; Rezaeyan, A.; Norouzi, F.; Rezapoor, S.; Abdollahi, H. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: clinical implications. Int. J. Radiat. Biol., 2018, 94(4), 335-356.
[http://dx.doi.org/10.1080/09553002.2018.1440092] [PMID: 29504497]
[41]
Mortezaee, K.; Najafi, M. Immune system in cancer radiotherapy: Resistance mechanisms and therapy perspectives. Crit. Rev. Oncol. Hematol., 2021, 157, 103180.
[http://dx.doi.org/10.1016/j.critrevonc.2020.103180] [PMID: 33264717]
[42]
Ashrafizadeh, M.; Farhood, B.; Eleojo Musa, A.; Taeb, S.; Rezaeyan, A.; Najafi, M. Abscopal effect in radioimmunotherapy. Int. Immunopharmacol., 2020, 85, 106663.
[http://dx.doi.org/10.1016/j.intimp.2020.106663] [PMID: 32521494]
[43]
Ashrafizadeh, M.; Farhood, B.; Eleojo Musa, A.; Taeb, S.; Najafi, M. Damage-associated molecular patterns in tumor radiotherapy. Int. Immunopharmacol., 2020, 86, 106761.
[http://dx.doi.org/10.1016/j.intimp.2020.106761] [PMID: 32629409]
[44]
Li, H.; Gupta, S.; Du, W.W.; Yang, B.B. MicroRNA-17 inhibits tumor growth by stimulating T-cell mediated host immune response. Oncoscience, 2014, 1(7), 531-539.
[http://dx.doi.org/10.18632/oncoscience.69] [PMID: 25594054]
[45]
Ventura, A.; Young, A.G.; Winslow, M.M.; Lintault, L.; Meissner, A.; Erkeland, S.J.; Newman, J.; Bronson, R.T.; Crowley, D.; Stone, J.R.; Jaenisch, R.; Sharp, P.A.; Jacks, T. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell, 2008, 132(5), 875-886.
[http://dx.doi.org/10.1016/j.cell.2008.02.019] [PMID: 18329372]
[46]
Wei, J.; Wang, F.; Kong, L.Y.; Xu, S.; Doucette, T.; Ferguson, S.D.; Yang, Y.; McEnery, K.; Jethwa, K.; Gjyshi, O.; Qiao, W.; Levine, N.B.; Lang, F.F.; Rao, G.; Fuller, G.N.; Calin, G.A.; Heimberger, A.B. miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. Cancer Res., 2013, 73(13), 3913-3926.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-4318] [PMID: 23636127]
[47]
Lin, R.; Chen, L.; Chen, G.; Hu, C.; Jiang, S.; Sevilla, J.; Wan, Y.; Sampson, J.H.; Zhu, B.; Li, Q.J. Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression. J. Clin. Invest., 2014, 124(12), 5352-5367.
[http://dx.doi.org/10.1172/JCI76561] [PMID: 25347474]

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