Abstract
Introduction
MicroRNAs are regulatory non-coding RNAs, with their outstanding regulatory mechanism, that make them potential biomarker for disease detection and therapeutics. They play an important role in pathological state, such as cancer by acting as oncogenic microRNAs and tumor suppressor microRNAs. The expression of microRNA-206, microRNA-4477a, microRNA-4795-5p, microR-4796-3p, microRNA-451b, and microRNA-4311 has proven to be deregulated in different cancer studies. However, no comprehensive study has been reported yet regarding their role in glioma patients.
Aim
The present study is designed to examine the expression profiling of microRNAs, such as microRNA-206, microRNA-4477a, microRNA-4795-5p, microR-4796-3p, microRNA-451b, and microRNA-4311 in glioma patients. Furthermore, the expression deregulation of selected microRNAs was correlated with oxidative stress and proliferation rate in glioma patients.
Methods
For this purpose, 153 glioma tissue samples and 200 brain tissues from epilepsy patients (taken as controls) were collected in the present study. Expression analysis of selected microRNAs was carried out on collected samples using real-time PCR (qPCR). Oxidative stress and proliferation rate were measured by estimation of 8OXOG level and Ki-67 using the ELISA and IHC.
Results
Our results showed significant deregulation of microRNA-206 (p < 0.0001), microRNA-4477a (p < 0.01), microRNA-4311 (p < 0.0001), microRNA-4795-5p (p < 0.0001), microRNA-4796-3p (p < 0.0001), and microRNA-451b (p < 0.0001) in glioma patients compared to controls. However, significant upregulation of 8OXOG level (p < 0.0001) and Ki-67 (p < 0.0001) was observed in glioma patients compared to controls. Kaplan–Meier analysis showed that deregulated expression of selected microRNAs was associated with significant decrease in survival of glioma patients.
Conclusions
Our results demonstrated significant deregulation of selected microRNAs in glioma patients. This deregulated expression was found associated with significant increased risk of glioma and could be further developed as effective prognostic biomarker and therapeutic tool in said disease.
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References
An T, Fan T, Zhang XQ et al (2019) Comparison of alterations in miRNA expression in matched tissue and blood samples during spinal cord glioma progression. Sci Rep 9:1–13. https://doi.org/10.1038/s41598-019-42364-x
Ariya SS, James AR, Joseph B (2020) Computational analysis of oral cancer gene expression profile and identification of MiRNAs and their regulatory hub genes. J Comp Med Research 11:154–159. https://doi.org/10.5455/jcmr.2020.11.03.19
Babu KR, Tay Y (2019) The Yin–Yang regulation of reactive oxygen species and microRNAs in cancer. Int J Mol Sci 20(21):5335
Banelli B, Forlani A, Allemanni G et al (2017) MicroRNA in glioblastoma: an overview. Int J Genom. https://doi.org/10.1155/2017/7639084
Borzabadi D, Hassan F, Behrouz A (2021) The effect of hsa-miR-451b knockdown on biological functions of gastric cancer stem-like cells. Biochem Genet. https://doi.org/10.1007/s10528-021-10057-8
Catania A, Maira F, Skarmoutsou E et al (2012) Insight into the role of microRNAs in brain tumors (review). Int J Oncol 40(3):605–624. https://doi.org/10.3892/ijo.2011.1305
Chen X, Wang Q, Wang J (2019) MiR-206 inhibits proliferation, migration, and invasion of gastric cancer cells by targeting the MUC1 gene. Oncotargets Ther 12:849–859. https://doi.org/10.2147/2FOTT.S180021
Gopalakrishnan C, Kamaraj B, Purohit R (2014) Mutations in microRNA binding sites of CEP genes involved in cancer. Cell Biochem Biophys 70(3):1933–1942. https://doi.org/10.1007/s12013-014-0153-8
Hosseinahli N, Aghapour M, Duijf PHG, Baradaran B (2018) Treating cancer with microRNA replacement therapy: a literature review. J Cell Physiol 233:5574–5588. https://doi.org/10.1002/jcp.26514
Ivkovic TC, Voss G, Cornella H et al (2017) microRNAs as cancer therapeutics: a step closer to clinical application. Cancer Lett 407:113–122
Kumar A, Rajendran V (2013) CEP proteins: the knights of centrosome dynasty. Protoplasma 250(5):965–983. https://doi.org/10.1007/s00709-013-0488-9
Lee ST, Chu K, Jung KH et al (2012) MiR-206 regulates brain-derived neurotrophic factor in Alzheimer disease model. Ann Neurol 72:269–277. https://doi.org/10.1002/ana.23588
Ma Y, Pan X, Xu P et al (2017) Plasma microRNA alterations between EGFR-activating mutational NSCLC patients with and without primary resistance to TKI. Oncotarget 8:88529–88536. https://doi.org/10.18632/2Foncotarget.19874
Mahjabeen I, Baig RM, Sabir M, Kayani MA (2013) Genetic and expressional variations of APEX1 are associated with increased risk of head and neck cancer. Mutagenesis 28:213–218. https://doi.org/10.1093/mutage/ges074
Mahjabeen I, Maqsood Y, Abbasi R et al (2021) Polymorphism in miRNA target sites of CEP-63 and CEP-152 ring complex influences expression of CEP genes and favors tumorigenesis in glioma. Future Oncol 17:3355–3372. https://doi.org/10.2217/fon-2020-1034
Mamoori A, Wahab R, Vider J et al (2019) The tumour suppressor effects and regulation of cancer stem cells by macrophage migration inhibitory factor targeted miR-451 in colon cancer. Gene 697:165–174. https://doi.org/10.1016/j.gene.2019.02.046
Mandujano-tinoco EA, Garc A, Mu L et al (2017) miRNA expression profile in multicellular breast cancer spheroids. BBA Mol Cell Res 1864(10):1642–1655. https://doi.org/10.1016/j.bbamcr.2017.05.023
Meister G, Landthaler M, Patkaniowska A et al (2004) Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell 15(2):185–197
Mihály D, Papp G, Mervai Z et al (2018) The oncomir face of microRNA-206: a permanent miR-206 transfection study. Exp Biol Med 243:1014–1023. https://doi.org/10.1177/1535370218795406
Moore LM, Zhang W (2010) Targeting miR-21 in glioma: a small RNA with big potential. Expert Opin Ther Targets 14:1247–1257. https://doi.org/10.1517/14728222.2010.527334
Mullany LE, Herrick JS, Wolff RK et al (2016) Association of cigarette smoking and microRNA expression in rectal cancer : Insight into tumor phenotype. Cancer Epidemiol 45:98–107. https://doi.org/10.1016/j.canep.2016.10.011
Nie JH, Li TX, Zhang XQ et al (2019) Roles of non-coding RNAs in normal human brain development, brain tumor, and neuropsychiatric disorders. Non-Coding RNA 5(2):36. https://doi.org/10.3390/ncrna5020036
Nouraee SKN, Mowla AMSJ (2016) A novel signaling role for miR-451 in esophageal tumor microenvironment and its contribution to tumor progression. Clin Transl Oncol 9:630–640. https://doi.org/10.1007/s12094-016-1575-0
Piletič K, Kunej T (2016) MicroRNA epigenetic signatures in human disease. Arch Toxicol 90:2405–2419. https://doi.org/10.1007/s00204-016-1815-7
Portnoy V, Huang V, Place RF et al (2011) Small RNA and transcriptional upregulation. Wiley Interdiscip Rev RNA 2(5):748–760
Ruan K, Fang X, Ouyang G (2009) MicroRNAs: novel regulators in the hallmarks of human cancer. Cancer Lett 285(2):116–126
Salehi Z, Hadadi P, Tavallaei O (2019) Prediction of biomarker miRNAs signature in colorectal cancer metastasis to liver cancer. Electron J Gen Med 16:1–11. https://doi.org/10.29333/ejgm/93467
Sen S, Dey A, Maulik U (2018) Identifying potential hubs for kidney renal clear cell carcinoma from TF-miRNA-gene regulatory networks. IEEE Appl Signal Process Conf 2018:240–244. https://doi.org/10.1109/ASPCON.2018.8748806
Shan ZX, Lin QX, Fu YH et al (2009) Upregulated expression of miR-1/miR-206 in a rat model of myocardial infarction. Biochem Biophys Res Commun 381:597–601. https://doi.org/10.1016/j.bbrc.2009.02.097
Silber J, James CD, Hodgson JG (2009) microRNAs in gliomas: small regulators of a big problem. Neuromol Med 11:208–222. https://doi.org/10.1007/s12017-009-8087-9
Slattery ML, Herrick JS, Pellatt DF et al (2016) MicroRNA profiles in colorectal carcinomas, adenomas and normal colonic mucosa: variations in miRNA expression and disease progression. Carcinogenesis 37:245–261. https://doi.org/10.1093/carcin/bgv249
Søkilde R, Persson H, Ehinger A et al (2019) Refinement of breast cancer molecular classification by miRNA expression profiles. BMC Genom 20(1):1–2
Svoronos AA, Engelman DM, Slack FJ (2016) OncomiR or tumor suppressor? The duplicity of MicroRNAs in cancer. Can Res 76:3666–3670. https://doi.org/10.1158/0008-5472.CAN-16-0359
Tao L, Zeng Y, Wang J et al (2015) Differential microRNA expression in aristolochic acid-induced upper urothelial tract cancers ex vivo. Mol Med Rep 12(5):6533–6546
Usuba W, Urabe F, Yamamoto Y et al (2018) Circulating miRNA panels for specific and early detection in bladder cancer. Cancer Sci 110:408–419. https://doi.org/10.1111/cas.13856
Wang WY, Lu WC (2020) Reduced expression of hsa-mir-338-3p contributes to the development of glioma cells by targeting mitochondrial 3-oxoacyl-acp synthase (Oxsm) in glioblastoma (gbm). Onco Targets Ther 13:9513–9523. https://doi.org/10.2147/OTT.S262873
Wang BC, Ma J (2015) Role of microRNAs in malignant glioma. Chin Med J (engl) 128:1238–1244. https://doi.org/10.4103/0366-6999.156141
Wang Y, Tian Y (2018) miR-206 inhibits cell proliferation, migration, and invasion by targeting BAG3 in human cervical cancer. Oncol Res 26:923–931. https://doi.org/10.3727/2F096504017X15143731031009
Wang X, Jiang D, Xu C et al (2017) Differential expression profile analysis of miRNAs with HER-2 overexpression and intervention in breast cancer cells. Int J Clin Exp Pathol 10(5):5039–5062
Wang Y, Xu H, Si L et al (2018) MiR-206 inhibits proliferation and migration of prostate cancer cells by targeting CXCL11. Prostate 78:479–490. https://doi.org/10.1002/pros.23468
Xia J, Luo M, Dai L et al (2021) Serum exosomal microRNAs as predictive markers for EGFR mutations in non-smallcell lung cancer. J Clin Lab Anal 35:1–12. https://doi.org/10.1002/jcla.23743
Xu XH, Wu XB, Wu SB et al (2014) Identification of mirnas differentially expressed in clinical stages of human colorectal carcinoma-an investigation in Guangzhou, China. PLoS One 9(4):1–9
Yamada Y, Arai T, Sugawara S et al (2018) Impact of novel oncogenic pathways regulated by antitumor miR-451a in renal cell carcinoma. In Cancer Sci 109:1239–1253. https://doi.org/10.1111/cas.13526
Yang Q, Zhang L, Zhong Y et al (2019) miR-206 inhibits cell proliferation, invasion, and migration by down-regulating PTP1B in hepatocellular carcinoma. Biosci Rep. https://doi.org/10.1042/BSR20181823
Zhang X, Li W (2012) 5-Fluorouracil in combination with cisplatin alters the microRNA expression profile in the CNE nasopharyngeal carcinoma cell line. Mol Med Rep 6(2):303–308
Zhao Y, Cui X, Zhu W et al (2017) Synergistic regulatory effects of microRNAs on brain glioma cells. Mol Med Rep 16:1409–1416. https://doi.org/10.3892/mmr.2017.6709
Acknowledgements
The authors acknowledge financial and infrastructural help from Higher Education Commission of Pakistan (HEC) and COMSATS University, Islamabad. The authors are thankful to patients and staff of Pakistan institute of medical sciences (PIMS), Islamabad, for contribution in this research.
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Communicated by Shuhua Xu.
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Masood, Y., Shal, M., Shah, M.F. et al. Dysregulated expression of microRNAs acts as prognostic and diagnostic biomarkers for glioma patients. Mol Genet Genomics 297, 1389–1401 (2022). https://doi.org/10.1007/s00438-022-01927-w
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DOI: https://doi.org/10.1007/s00438-022-01927-w