Circulating serum oncologic miRNA in pediatric juvenile pilocytic astrocytoma patients predicts mural nodule volume
Juvenile pilocytic astrocytomas represent the largest group of pediatric brain tumors. The ideal management for these tumors is early, total surgical resection. To detect and track treatment response, a screening tool is needed to identify patients for surgical evaluation and assess the quality of treatment. The identification of aberrant miRNA profiles in the sera of juvenile pilocytic astrocytoma patients could provide such a screening tool.
The authors reviewed the serum profiles of 84 oncologically relevant miRNAs in pediatric juvenile pilocytic astrocytoma patients via qPCR screening.
miR-21, miR-15b, miR-23a, and miR-146b were significantly elevated in the sera of JPA patients as compared to non-oncologic controls, oncologic controls, and post-JPA resection samples (p < 0.001, 0.022, 0.034, 0.044). miR-21 had the highest AUC on ROC analysis (AUC > 0.99, sensitivity 75%, specificity 100%). All four miRNAs also correlated well with tumor mural nodule size, though they only poorly correlated with total tumor size, including cystic components (Spearman’s R2: miR-21 91.7 vs 6.9%, miR-15b 86.3 vs 23.1%, miR-23a 85.8 vs 23.0%, miR-146b 59.8 vs 11.9%).
In this small pilot study, pediatric juvenile pilocytic astrocytoma patients had significant elevations in serum miR-21, miR-15b, miR-23a, and miR-146b levels that do not appear to be driven by hydrocephalus or local distortion of the intracranial contents. These alterations correlate with solid tumor component volume and reverse with complete tumor resection, suggesting that this serum miRNA profile may delineate biomarkers for screening and tracking juvenile pilocytic astrocytoma patients. Additional studies, with a larger cohort, are needed to verify these results.
KeywordsBiomarker Juvenile pilocytic astrocytoma miRNA Serum Ependymoma
The authors would also like to thank Paul Kanev, MD, Jon Martin, MD, and Petronella Stoltz, APRN of the Connecticut Children’s Medical Center Division of Neurosurgery for their participation in screening and accruing patients. We would also like to thank Todd Jensen, MS for his technical assistance with specimen processing.
The Connecticut Brain Tumor Alliance and the Somberg Family provided financial support in the form of generous gifts in support of pediatric brain cancer research.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Connecticut Children’s Medical Center Institutional Review Board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 2.Au Yeung CL, Co NN, Tsuruga T, Yeung TL, Kwan SY, Leung CS, Li Y, Lu ES, Kwan K, Wong KK, Schmandt R, Lu KH, Mok SC (2016) Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun 7:11150. https://doi.org/10.1038/ncomms11150 CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Cao Y, Green K, Quattlebaum S, Milam B, Lu L, Gao D, He H, Li N, Gao L, Hall F, Whinery M, Handley E, Ma Y, Xu T, Jin F, Xiao J, Wei M, Smith D, Bornstein S, Gross N, Pyeon D, Song J, Lu SL (2018) Methylated genomic loci encoding microRNA as a biomarker panel in tissue and saliva for head and neck squamous cell carcinoma. Clin Epigenetics 10:43. https://doi.org/10.1186/s13148-018-0470-7 CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Correa-Gallego C, Maddalo D, Doussot A, Kemeny N, Kingham TP, Allen PJ, D'Angelica MI, DeMatteo RP, Betel D, Klimstra D, Jarnagin WR, Ventura A (2016) Circulating plasma levels of MicroRNA-21 and MicroRNA-221 are potential diagnostic markers for primary intrahepatic cholangiocarcinoma. PLoS One 11:e0163699. https://doi.org/10.1371/journal.pone.0163699 CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Gai C, Camussi F, Broccoletti R, Gambino A, Cabras M, Molinaro L, Carossa S, Camussi G, Arduino PG (2018) Salivary extracellular vesicle-associated miRNAs as potential biomarkers in oral squamous cell carcinoma. BMC Cancer 18:439. https://doi.org/10.1186/s12885-018-4364-z CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Hsiao YC, Chu LJ, Chen YT, Chi LM, Chien KY, Chiang WF, Chang YT, Chen SF, Wang WS, Chuang YN, Lin SY, Chien CY, Chang KP, Chang YS, Yu JS (2018) Variability assessment of 90 salivary proteins in intraday and interday samples from healthy donors by multiple reaction monitoring-mass spectrometry. Proteomics Clin Appl 12. https://doi.org/10.1002/prca.201700039
- 20.Kan X, Sun Y, Lu J, Li M, Wang Y, Li Q, Liu Y, Liu M, Tian L (2016) Co-inhibition of miRNA-21 and miRNA-221 induces apoptosis by enhancing the p53-mediated expression of pro-apoptotic miRNAs in laryngeal squamous cell carcinoma. Mol Med Rep 13:4315–4320. https://doi.org/10.3892/mmr.2016.5048 CrossRefPubMedGoogle Scholar
- 22.Lee JC, Zhao JT, Clifton-Bligh RJ, Gill A, Gundara JS, Ip JC, Glover A, Sywak MS, Delbridge LW, Robinson BG, Sidhu SB (2013) MicroRNA-222 and microRNA-146b are tissue and circulating biomarkers of recurrent papillary thyroid cancer. Cancer 119:4358–4365. https://doi.org/10.1002/cncr.28254 CrossRefPubMedGoogle Scholar
- 23.Lee TJ, Yoo JY, Shu D, Li H, Zhang J, Yu JG, Jaime-Ramirez AC, Acunzo M, Romano G, Cui R, Sun HL, Luo Z, Old M, Kaur B, Guo P, Croce CM (2017) RNA nanoparticle-based targeted therapy for glioblastoma through inhibition of oncogenic miR-21. Mol Ther https://doi.org/10.1016/j.ymthe.2016.11.016
- 27.Li Y, Wang Y, Yu L, Sun C, Cheng D, Yu S, Wang Q, Yan Y, Kang C, Jin S, An T, Shi C, Xu J, Wei C, Liu J, Sun J, Wen Y, Zhao S, Kong Y (2013) miR-146b-5p inhibits glioma migration and invasion by targeting MMP16. Cancer Lett 339:260–269. https://doi.org/10.1016/j.canlet.2013.06.018 CrossRefPubMedGoogle Scholar
- 28.Liu AM, Yao TJ, Wang W, Wong KF, Lee NP, Fan ST, Poon RT, Gao C, Luk JM (2012) Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study. BMJ Open 2:e000825. https://doi.org/10.1136/bmjopen-2012-000825 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Mima K, Nishihara R, Nowak JA, Kim SA, Song M, Inamura K, Sukawa Y, Masuda A, Yang J, Dou R, Nosho K, Baba H, Giovannucci EL, Bowden M, Loda M, Giannakis M, Bass AJ, Dranoff G, Freeman GJ, Chan AT, Fuchs CS, Qian ZR, Ogino S (2016) MicroRNA MIR21 and T cells in colorectal cancer. Cancer Immunol Res 4:33–40. https://doi.org/10.1158/2326-6066.CIR-15-0084 CrossRefPubMedGoogle Scholar
- 32.Mima K, Nishihara R, Yang J, Dou R, Masugi Y, Shi Y, da Silva A, Cao Y, Song M, Nowak J, Gu M, Li W, Morikawa T, Zhang X, Wu K, Baba H, Giovannucci EL, Meyerhardt JA, Chan AT, Fuchs CS, Qian ZR, Ogino S (2016) MicroRNA MIR21 (miR-21) and PTGS2 expression in colorectal cancer and patient survival. Clin Cancer Res 22:3841–3848. https://doi.org/10.1158/1078-0432.CCR-15-2173 CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Nolen BM, Orlichenko LS, Marrangoni A, Velikokhatnaya L, Prosser D, Grizzle WE, Ho K, Jenkins FJ, Bovbjerg DH, Lokshin AE (2013) An extensive targeted proteomic analysis of disease-related protein biomarkers in urine from healthy donors. PLoS One 8:e63368. https://doi.org/10.1371/journal.pone.0063368 CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Nonaka T, Wong DTW (2018) Liquid biopsy in head and neck cancer: promises and challenges. J Dent Res:22034518762071. https://doi.org/10.1177/0022034518762071
- 37.Ogata-Kawata H, Izumiya M, Kurioka D, Honma Y, Yamada Y, Furuta K, Gunji T, Ohta H, Okamoto H, Sonoda H, Watanabe M, Nakagama H, Yokota J, Kohno T, Tsuchiya N (2014) Circulating exosomal microRNAs as biomarkers of colon cancer. PLoS One 9:e92921. https://doi.org/10.1371/journal.pone.0092921 CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Olivieri F, Spazzafumo L, Bonafè M, Recchioni R, Prattichizzo F, Marcheselli F, Micolucci L, Mensà E, Giuliani A, Santini G, Gobbi M, Lazzarini R, Boemi M, Testa R, Antonicelli R, Procopio AD, Bonfigli AR (2015) MiR-21-5p and miR-126a-3p levels in plasma and circulating angiogenic cells: relationship with type 2 diabetes complications. Oncotarget 6:35372–35382. https://doi.org/10.18632/oncotarget.6164 PubMedPubMedCentralGoogle Scholar
- 39.Pellatt DF, Stevens JR, Wolff RK, Mullany LE, Herrick JS, Samowitz W, Slattery ML (2016) Expression profiles of miRNA subsets distinguish human colorectal carcinoma and normal colonic mucosa. Clin Transl Gastroenterol 7:e152. https://doi.org/10.1038/ctg.2016.11 CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Piepoli A, Tavano F, Copetti M, Mazza T, Palumbo O, Panza A, di Mola FF, Pazienza V, Mazzoccoli G, Biscaglia G, Gentile A, Mastrodonato N, Carella M, Pellegrini F, di Sebastiano P, Andriulli A (2012) Mirna expression profiles identify drivers in colorectal and pancreatic cancers. PLoS One 7:e33663. https://doi.org/10.1371/journal.pone.0033663 CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Prabowo AS, van Scheppingen J, Iyer AM, Anink JJ, Spliet WG, van Rijen PC, Schouten-van Meeteren AY, Aronica E (2015) Differential expression and clinical significance of three inflammation-related microRNAs in gangliogliomas. J Neuroinflammation 12:97. https://doi.org/10.1186/s12974-015-0315-7 CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Pricola Fehnel K, Duggins-Warf M, Zurakowski D, McKee-Proctor M, Majumder R, Raber M, Han X, Smith ER (2016) Using urinary bFGF and TIMP3 levels to predict the presence of juvenile pilocytic astrocytoma and establish a distinct biomarker signature. J Neurosurg Pediatr 18:396–407. https://doi.org/10.3171/2015.12.PEDS15448 CrossRefPubMedGoogle Scholar
- 47.Regazzo G, Terrenato I, Spagnuolo M, Carosi M, Cognetti G, Cicchillitti L, Sperati F, Villani V, Carapella C, Piaggio G, Pelosi A, Rizzo MG (2016) A restricted signature of serum miRNAs distinguishes glioblastoma from lower grade gliomas. J Exp Clin Cancer Res 35:124. https://doi.org/10.1186/s13046-016-0393-0 CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Rui M, Qu Y, Gao T, Ge Y, Feng C, Xu X (2017) Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells. Int J Nanomedicine 12:217–237. https://doi.org/10.2147/IJN.S122171 CrossRefPubMedGoogle Scholar
- 49.Sierzega M, Kaczor M, Kolodziejczyk P, Kulig J, Sanak M, Richter P (2017) Evaluation of serum microRNA biomarkers for gastric cancer based on blood and tissue pools profiling: the importance of miR-21 and miR-331. Br J Cancer 117:266–273. https://doi.org/10.1038/bjc.2017.190 CrossRefPubMedPubMedCentralGoogle Scholar
- 51.Sun M, Song J, Zhou Z, Zhu R, Jin H, Ji Y, Lu Q, Ju H (2016) comparison of serum MicroRNA21 and tumor markers in diagnosis of early non-small cell lung cancer. Dis Markers 2016:3823121. https://doi.org/10.1155/2016/3823121
- 55.van Scheppingen J, Iyer AM, Prabowo AS, Mühlebner A, Anink JJ, Scholl T, Feucht M, Jansen FE, Spliet WG, Krsek P, Zamecnik J, Buccoliero AM, Giordano F, Genitori L, Kotulska K, Jozwiak S, Jaworski J, Liszewska E, van Vliet EA, Aronica E (2016) Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA-derived cell cultures. Glia 64:1066–1082. https://doi.org/10.1002/glia.22983 PubMedGoogle Scholar
- 56.Wang JH, Zhou WW, Cheng ST, Liu BX, Liu FR, Song JQ (2015) Downregulation of sprouty homolog 2 by microRNA-21 inhibits proliferation, metastasis and invasion, however promotes the apoptosis of multiple myeloma cells. Mol Med Rep 12:1810–1816. https://doi.org/10.3892/mmr.2015.3567 CrossRefPubMedPubMedCentralGoogle Scholar
- 57.Wang W, Li W, Ding M, Yuan H, Yang J, Meng W, Jin E, Wang X, Ma S (2016) Identification of miRNAs as non-invasive biomarkers for early diagnosis of lung cancers. Tumour Biol. https://doi.org/10.1007/s13277-016-5442-y
- 62.Yang C, Wang C, Chen X, Chen S, Zhang Y, Zhi F, Wang J, Li L, Zhou X, Li N, Pan H, Zhang J, Zen K, Zhang CY, Zhang C (2013) Identification of seven serum microRNAs from a genome-wide serum microRNA expression profile as potential noninvasive biomarkers for malignant astrocytomas. Int J Cancer 132:116–127. https://doi.org/10.1002/ijc.27657 CrossRefPubMedGoogle Scholar
- 67.Zhang W, Ni M, Su Y, Wang H, Zhu S, Zhao A, Li G (2016) MicroRNAs in serum exosomes as potential biomarkers in clear-cell renal cell carcinoma. Eur Urol Focus https://doi.org/10.1016/j.euf.2016.09.007