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Journal of Neuro-Oncology

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Open Access 01-09-2018 | Laboratory Investigation

MicroRNA-1231 exerts a tumor suppressor role through regulating the EGFR/PI3K/AKT axis in glioma

Authors: Jiale Zhang, Jie Zhang, Wenjin Qiu, Jian Zhang, Yangyang Li, Enjun Kong, Ailin Lu, Jia Xu, Xiaoming Lu

Published in: Journal of Neuro-Oncology | Issue 3/2018

Abstract

Purpose

MicroRNAs (miRNAs) have been shown to be involved in the initiation and progression of glioma. However, the underlying molecular mechanisms are still unclear.

Methods

We performed microarray analysis to evaluate miRNA expression levels in 158 glioma tissue samples, and examined miR-1231 levels in glioma samples and healthy brain tissues using qRT-PCR. In vitro analyses were performed using miR-1231 mimics, inhibitors, and siRNA targeting EGFR. We used flow cytometry, CCK-8 assays, and colony formation assays to examine glioma proliferation and cell cycle analysis. A dual luciferase reporter assay was performed to examine miR-1231 regulation of EGFR, and the effect of upregulated miR-1231 was investigated in a subcutaneous GBM model.

Results

We found that miR-1231 expression was decreased in human glioma tissues and negatively correlated with EGFR levels. Moreover, the downregulation of miR-1231 negatively correlated with the clinical stage of human glioma patients. miR-1231 overexpression dramatically downregulated glioma cell proliferation, and suppressed tumor growth in a nude mouse model. Bioinformatics prediction and a luciferase assay confirmed EGFR as a direct target of miR-1231. EGFR overexpression abrogated the suppressive effect of miR-1231 on the PI3K/AKT pathway and G1 arrest.

Conclusions

Taken together, these results demonstrated that EGFR is a direct target of miR-1231. Our findings suggest that the miR-1231/EGFR axis may be a helpful future diagnostic target for malignant glioma.

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Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS (2017) CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro-oncology 19(suppl_5):v1–v88. https://doi.org/10.1093/neuonc/nox158 CrossRefPubMed

Bing ZT, Yang GH, Xiong J, Guo L, Yang L (2016) Identify signature regulatory network for glioblastoma prognosis by integrative mRNA and miRNA co-expression analysis. IET Syst Biol 10(6):244–251. https://doi.org/10.1049/iet-syb.2016.0004 CrossRefPubMed

Ostrom QT, Gittleman H, Stetson L, Virk SM, Barnholtz-Sloan JS (2015) Epidemiology of gliomas. Cancer Treat Res 163:1–14. https://doi.org/10.1007/978-3-319-12048-5_1 CrossRefPubMed

Holland EC (2000) Glioblastoma multiforme: the terminator. Proc Natl Acad Sci USA 97(12):6242–6244CrossRefPubMed

Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233. https://doi.org/10.1016/j.cell.2009.01.002 CrossRefPubMedPubMedCentral

Lujambio A, Lowe SW (2012) The microcosmos of cancer. Nature 482(7385):347–355. https://doi.org/10.1038/nature10888 CrossRefPubMedPubMedCentral

Janga SC, Vallabhaneni S (2011) MicroRNAs as post-transcriptional machines and their interplay with cellular networks. Adv Exp Med Biol 722:59–74. https://doi.org/10.1007/978-1-4614-0332-6_4 CrossRefPubMed

Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6(11):857–866. https://doi.org/10.1038/nrc1997 CrossRefPubMed

Ambros V (2004) The functions of animal microRNAs. Nature 431(7006):350–355. https://doi.org/10.1038/nature02871 CrossRefPubMed

10.

Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297CrossRefPubMed

11.

Malzkorn B, Wolter M, Liesenberg F, Grzendowski M, Stuhler K, Meyer HE, Reifenberger G (2010) Identification and functional characterization of microRNAs involved in the malignant progression of gliomas. Brain Pathol (Zurich Switzerland) 20(3):539–550. https://doi.org/10.1111/j.1750-3639.2009.00328.x CrossRef

12.

Zhou C, Yu Q, Chen L, Wang J, Zheng S, Zhang J (2012) A miR-1231 binding site polymorphism in the 3′UTR of IFNAR1 is associated with hepatocellular carcinoma susceptibility. Gene 507(1):95–98. https://doi.org/10.1016/j.gene.2012.06.073 CrossRefPubMed

13.

Kohno T, Tsuge M, Murakami E, Hiraga N, Abe H, Miki D, Imamura M, Ochi H, Hayes CN, Chayama K (2014) Human microRNA hsa-miR-1231 suppresses hepatitis B virus replication by targeting core mRNA. J Viral Hepat 21(9):e89–e97. https://doi.org/10.1111/jvh.12240 CrossRef

14.

Yarden Y, Ullrich A (1988) Growth factor receptor tyrosine kinases. Annu Rev Biochem 57:443–478. https://doi.org/10.1146/annurev.bi.57.070188.002303 CrossRefPubMed

15.

Scagliotti GV, Selvaggi G, Novello S, Hirsch FR (2004) The biology of epidermal growth factor receptor in lung cancer. Clin Cancer Res 10(12 Pt 2):4227s–4232s. https://doi.org/10.1158/1078-0432.ccr-040007 CrossRef

16.

Gao Y, Yu H, Liu Y, Liu X, Zheng J, Ma J, Gong W, Chen J, Zhao L, Tian Y, Xue Y (2017) Long Non-coding RNA HOXA-AS2 regulates malignant glioma behaviors and vasculogenic mimicry formation via the MiR-373/EGFR axis. Cell Physiol Biochem 45 (1):131–147. https://doi.org/10.1159/000486253 CrossRefPubMed

17.

Mizoguchi M, Betensky RA, Batchelor TT, Bernay DC, Louis DN, Nutt CL (2006) Activation of STAT3, MAPK, and AKT in malignant astrocytic gliomas: correlation with EGFR status, tumor grade, and survival. J Neuropathol Exp Neurol 65(12):1181–1188. https://doi.org/10.1097/01.jnen.0000248549.14962.b2 CrossRefPubMed

18.

Gan Y, Shi C, Inge L, Hibner M, Balducci J, Huang Y (2010) Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells. Oncogene 29(35):4947–4958CrossRefPubMed

19.

Carpenter RL, Jiang BH (2013) Roles of EGFR, PI3K, AKT, and mTOR in heavy metal-induced cancer. Curr Cancer Drug Targ 13(3):252–266CrossRef

20.

Su CC, Chiu TL (2016) Tanshinone IIA decreases the protein expression of EGFR, and IGFR blocking the PI3K/Akt/mTOR pathway in gastric carcinoma AGS cells both in vitro and in vivo. Oncol Rep 36(2):1173–1179. https://doi.org/10.3892/or.2016.4857 CrossRefPubMed

21.

Zhang L, Wang H, Zhu J, Xu J, Ding K (2014) Mollugin induces tumor cell apoptosis and autophagy via the PI3K/AKT/mTOR/p70S6K and ERK signaling pathways. Biochem Biophys Res Commun 450(1):247–254. https://doi.org/10.1016/j.bbrc.2014.05.101 CrossRefPubMed

22.

Doherty L, Gigas DC, Kesari S, Drappatz J, Kim R, Zimmerman J, Ostrowsky L, Wen PY (2006) Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Neurology 67(1):156–158. https://doi.org/10.1212/01.wnl.0000223844.77636.29 CrossRefPubMed

23.

Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. New Engl J Med 362(25):2380–2388. https://doi.org/10.1056/NEJMoa0909530 CrossRefPubMed

24.

Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, Allen B, Bozic I, Reiter JG, Nowak MA, Kinzler KW, Oliner KS, Vogelstein B (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486(7404):537–540. https://doi.org/10.1038/nature11219 CrossRefPubMedPubMedCentral

25.

Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, Lao KQ, Livak KJ, Guegler KJ (2005) Real-time quantification of microRNAs by stem-loop RT-PCR. Nucl Acids Res 33(20):e179. https://doi.org/10.1093/nar/gni178 CrossRefPubMed

26.

Qian X, Yu J, Yin Y, He J, Wang L, Li Q, Zhang LQ, Li CY, Shi ZM, Xu Q, Li W, Lai LH, Liu LZ, Jiang BH (2013) MicroRNA-143 inhibits tumor growth and angiogenesis and sensitizes chemosensitivity to oxaliplatin in colorectal cancers. Cell Cycle (Georgetown Tex) 12(9):1385–1394. https://doi.org/10.4161/cc.24477 CrossRef

27.

Wang H, Wu W, Wang HW, Wang S, Chen Y, Zhang X, Yang J, Zhao S, Ding HF, Lu D (2010) Analysis of specialized DNA polymerases expression in human gliomas: association with prognostic significance. Neuro-oncology 12(7):679–686. https://doi.org/10.1093/neuonc/nop074 CrossRefPubMedPubMedCentral

28.

Shi Z, Chen Q, Li C, Wang L, Qian X, Jiang C, Liu X, Wang X, Li H, Kang C, Jiang T, Liu LZ, You Y, Liu N, Jiang BH (2014) MiR-124 governs glioma growth and angiogenesis and enhances chemosensitivity by targeting R-Ras and N-Ras. Neuro-oncology 16(10):1341–1353. https://doi.org/10.1093/neuonc/nou084 CrossRefPubMedPubMedCentral

29.

Peng Z, Wu T, Li Y, Xu Z, Zhang S, Liu B, Chen Q, Tian D (2016) MicroRNA-370-3p inhibits human glioma cell proliferation and induces cell cycle arrest by directly targeting beta-catenin. Brain Res 1644:53–61. https://doi.org/10.1016/j.brainres.2016.04.066 CrossRefPubMed

30.

Huang T, Kang W, Zhang B, Wu F, Dong Y, Tong JH, Yang W, Zhou Y, Zhang L, Cheng AS, Yu J, To KF (2016) miR-508-3p concordantly silences NFKB1 and RELA to inactivate canonical NF-kappaB signaling in gastric carcinogenesis. Mol Cancer 15:9. https://doi.org/10.1186/s12943-016-0493-7 CrossRefPubMedPubMedCentral

31.

Liu YL, Gao X, Jiang Y, Zhang G, Sun ZC, Cui BB, Yang YM (2015) Expression and clinicopathological significance of EED, SUZ12 and EZH2 mRNA in colorectal cancer. J Cancer Res Clin Oncol 141(4):661–669. https://doi.org/10.1007/s00432-014-1854-5 CrossRefPubMed

32.

Wu S, Lin Y, Xu D, Chen J, Shu M, Zhou Y, Zhu W, Su X, Zhou Y, Qiu P, Yan G (2012) MiR-135a functions as a selective killer of malignant glioma. Oncogene 31(34):3866–3874. https://doi.org/10.1038/onc.2011.551 CrossRefPubMed

33.

Cui R, Guan Y, Sun C, Chen L, Bao Y, Li G, Qiu B, Meng X, Pang C, Wang Y (2016) A tumor-suppressive microRNA, miR-504, inhibits cell proliferation and promotes apoptosis by targeting FOXP1 in human glioma. Cancer Lett 374(1):1–11. https://doi.org/10.1016/j.canlet.2016.01.051 CrossRefPubMed

34.

Zhang R, Luo H, Wang S, Chen Z, Hua L, Wang HW, Chen W, Yuan Y, Zhou X, Li D, Shen S, Jiang T, You Y, Liu N, Wang H (2015) MiR-622 suppresses proliferation, invasion and migration by directly targeting activating transcription factor 2 in glioma cells. J Neuro-oncol 121(1):63–72. https://doi.org/10.1007/s11060-014-1607-y CrossRef

35.

Song H, Zhang Y, Liu N, Zhang D, Wan C, Zhao S, Kong Y, Yuan L (2016) Let-7b inhibits the malignant behavior of glioma cells and glioma stem-like cells via downregulation of E2F2. J Physiol Biochem 72(4):733–744. https://doi.org/10.1007/s13105-016-0512-6 CrossRefPubMed

36.

Zhi T, Jiang K, Zhang C, Xu X, Wu W, Nie E, Yu T, Zhou X, Bao Z, Jin X, Zhang J, Wang Y, Liu N (2017) MicroRNA-1301 inhibits proliferation of human glioma cells by directly targeting N-Ras. Am J Cancer Res 7(4):982–998PubMedPubMedCentral

37.

De Luca A, Maiello MR, D’Alessio A, Pergameno M, Normanno N (2012) The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targ 16(Suppl 2):S17–S27. https://doi.org/10.1517/14728222.2011.639361 CrossRef

38.

Mendell JT (2005) MicroRNAs: critical regulators of development, cellular physiology and malignancy. Cell Cycle (Georgetown Tex) 4(9):1179–1184. https://doi.org/10.4161/cc.4.9.2032 CrossRef

39.

Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433(7027):769–773. https://doi.org/10.1038/nature03315 CrossRefPubMed

40.

Hata A, Kashima R (2016) Dysregulation of microRNA biogenesis machinery in cancer. Crit Rev Biochem Mol Biol 51(3):121–134. https://doi.org/10.3109/10409238.2015.1117054 CrossRefPubMed

41.

Schickel R, Boyerinas B, Park SM, Peter ME (2008) MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene 27(45):5959–5974. https://doi.org/10.1038/onc.2008.274 CrossRefPubMed

42.

Silber J, Lim D, Petritsch C, Persson A, Yu M, Vandenberg S, James C, Bergers G, Weiss W, Alvarezbuylla A (2008) miR-124a and miR-137 inhibit proliferation of GBM cells and induce differentiation of tumor stem cells. Can Res 68(24):14

43.

Kwak HJ, Kim YJ, Chun KR, Woo YM, Park SJ, Jeong JA, Jo SH, Kim TH, Min HS, Chae JS (2011) Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas. Oncogene 30(21):2433CrossRefPubMed

44.

Emdad L, Janjic A, Alzubi MA, Hu B, Santhekadur PK, Menezes ME, Shen XN, Das SK, Sarkar D, Fisher PB (2015) Suppression of miR-184 in malignant gliomas upregulates SND1 and promotes tumor aggressiveness. Neuro-oncology 17(3):419–429. https://doi.org/10.1093/neuonc/nou220 CrossRefPubMed

45.

Nielsen JS, Jakobsen E, Holund B, Bertelsen K, Jakobsen A (2004) Prognostic significance of p53, Her-2, and EGFR overexpression in borderline and epithelial ovarian cancer. Int J Gynecol Cancer 14(6):1086–1096. https://doi.org/10.1111/j.1048-891X.2004.14606.x CrossRefPubMed

46.

Bhargava R, Gerald WL, Li AR, Pan Q, Lal P, Ladanyi M, Chen B (2005) EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations. Mod Pathol 18(8):1027–1033. https://doi.org/10.1038/modpathol.3800438 CrossRefPubMed

47.

Lanaya H, Natarajan A, Komposch K, Li L, Amberg N, Chen L, Wculek SK, Hammer M, Zenz R, Peck-Radosavljevic M, Sieghart W, Trauner M, Wang H, Sibilia M (2014) EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nat Cell Biol 16(10):972–977. https://doi.org/10.1038/ncb3031 CrossRefPubMedPubMedCentral

48.

Zhou X, Ren Y, Moore L, Mei M, You Y, Xu P, Wang B, Wang G, Jia Z, Pu P, Zhang W, Kang C (2010) Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab Investig 90 (2):144–155. https://doi.org/10.1038/labinvest.2009.126 CrossRefPubMed

49.

Xu B, Wang N, Wang X, Tong N, Shao N, Tao J, Li P, Niu X, Feng N, Zhang L, Hua L, Wang Z, Chen M (2012) MiR-146a suppresses tumor growth and progression by targeting EGFR pathway and in a p-ERK-dependent manner in castration-resistant prostate cancer. Prostate 72(11):1171–1178. https://doi.org/10.1002/pros.22466 CrossRefPubMed

Title: MicroRNA-1231 exerts a tumor suppressor role through regulating the EGFR/PI3K/AKT axis in glioma
Authors: Jiale Zhang
Jie Zhang
Wenjin Qiu
Jian Zhang
Yangyang Li
Enjun Kong
Ailin Lu
Jia Xu
Xiaoming Lu
Publication date: 01-09-2018
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 3/2018
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-018-2903-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

MicroRNA-1231 exerts a tumor suppressor role through regulating the EGFR/PI3K/AKT axis in glioma

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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