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01-09-2013 | Laboratory Investigation

miR-124 radiosensitizes human glioma cells by targeting CDK4

Authors: Xubin Deng, Lei Ma, Minhua Wu, Gong Zhang, Chuan Jin, Yuping Guo, Ruilei Liu

Published in: Journal of Neuro-Oncology | Issue 3/2013

Abstract

The aberrant expression of cyclin-dependent kinase-4 (CDK4) has previously been observed in human brain glioma. Furthermore, it is observed that up-regulation of CDK4 is associated with therapy resistance and relapse. However, the mechanisms behind these phenomena remain unclear. Here, we demonstrated that elevated CDK4 expression is correlated with poor prognosis in glioma after radiotherapy and that CDK4 knockdown conferred radiosensitivity in glioma cell lines. CDK4 was identified as potential downstream target of miR-124 through bioinformatics analysis and dual-firefly luciferase reporter assay. Furthermore, restoration of miR-124 could confer radiosensitivity. Cell differentiation agent-2 (CDA-2) mimicked the effect of miR-124 restoration and CDK4 knockdown, and sensitized xenografts to radiation in an animal model. Our findings demonstrated for the first time that CDK4 was a downstream target of miR-124 and that CDA-2 could radiosensitize Glioblastoma multiforme cells through the MiR-124-CDK4 axis.

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DeAngelis LM (2001) Brain tumors. N Engl J Med 344:114–123PubMedCrossRef

Stupp R, Hegi ME, van den Bent MJ, Mason WP, Weller M et al (2006) Changing paradigms—an update on the multidisciplinary management of malignant glioma. Oncologist 11:165–180PubMedCrossRef

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRef

Mrugala MM, Chamberlain MC (2008) Mechanisms of disease: temozolomide and glioblastoma—look to the future. Nat Clin Pract Oncol 5:476–486PubMedCrossRef

Bertout JA, Patel SA, Simon MC (2008) The impact of O₂ availability on human cancer. Nat Rev Cancer 8:967–975PubMedCrossRef

(1995) Oncogenes: 20 years later. Genes Dev 9:1289–1301

Choudhury A, Cuddihy A, Bristow RG (2006) Radiation and new molecular agents part I: targeting ATM-ATR checkpoints, DNA repair, and the proteasome. Semin Radiat Oncol 16:51–58PubMedCrossRef

Johnson N, Shapiro GI (2012) Cyclin-dependent kinase 4/6 inhibition in cancer therapy. Cell Cycle 11:3913PubMedCrossRef

Ciznadija D, Liu Y, Pyonteck SM, Holland EC, Koff A (2011) Cyclin D1 and cdk4 mediate development of neurologically destructive oligodendroglioma. Cancer Res 71:6174–6183PubMedCrossRef

10.

Fiano V, Ghimenti C, Schiffer D (2003) Expression of cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors in oligodendrogliomas in humans. Neurosci Lett 347:111–115PubMedCrossRef

11.

Zhang X, Zhao M, Huang AY, Fei Z, Zhang W et al (2005) The effect of cyclin D expression on cell proliferation in human gliomas. J Clin Neurosci 12:166–168PubMedCrossRef

12.

Kim TJ, Lee JW, Song SY, Choi JJ, Choi CH et al (2006) Increased expression of pAKT is associated with radiation resistance in cervical cancer. Br J Cancer 94:1678–1682PubMed

13.

Tanno S, Yanagawa N, Habiro A, Koizumi K, Nakano Y et al (2004) Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance. Cancer Res 64:3486–3490PubMedCrossRef

14.

Bussink J, van der Kogel AJ, Kaanders JH (2008) Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol 9:288–296PubMedCrossRef

15.

Alt JR, Cleveland JL, Hannink M, Diehl JA (2000) Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev 14:3102–3114PubMedCrossRef

16.

Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA et al (1997) Identification of CDK4 sequences involved in cyclin D1 and p16 binding. J Biol Chem 272:18869–18874PubMedCrossRef

17.

Shimura T, Kakuda S, Ochiai Y, Kuwahara Y, Takai Y et al (2011) Targeting the AKT/GSK3beta/cyclin D1/Cdk4 survival signaling pathway for eradication of tumor radioresistance acquired by fractionated radiotherapy. Int J Radiat Oncol Biol Phys 80:540–548PubMedCrossRef

18.

He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5:522–531PubMedCrossRef

19.

Zhang H, Shykind B, Sun T (2012) Approaches to manipulating microRNAs in neurogenesis. Front Neurosci 6:196PubMed

20.

Schickel R, Boyerinas B, Park SM, Peter ME (2008) MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene 27:5959–5974PubMedCrossRef

21.

Cheng LC, Pastrana E, Tavazoie M, Doetsch F (2009) miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat Neurosci 12:399–408PubMedCrossRef

22.

Pierson J, Hostager B, Fan R, Vibhakar R (2008) Regulation of cyclin dependent kinase 6 by microRNA 124 in medulloblastoma. J Neurooncol 90:1–7PubMedCrossRef

23.

Xia H, Cheung WK, Ng SS, Jiang X, Jiang S et al (2012) Loss of brain-enriched miR-124 microRNA enhances stem-like traits and invasiveness of glioma cells. J Biol Chem 287:9962–9971PubMedCrossRef

24.

Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM et al (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–773PubMedCrossRef

25.

Yao CJ, Lai GM, Chan CF, Yang YY, Liu FC et al (2005) Differentiation of pheochromocytoma PC12 cells induced by human urine extract and the involvement of the extracellular signal-regulated kinase signaling pathway. J Altern Complement Med 11:903–908PubMedCrossRef

26.

Huang J, Yang M, Liu H, Jin J (2008) Human urine extract CDA-2 induces apoptosis of myelodysplastic syndrome-derived MUTZ-1 cells through the PI3K/Akt signaling pathway in a caspase-3-dependent manner. Acta Pharmacol Sin 29:951–964PubMedCrossRef

27.

Lin CL, Wang MH, Qin YF, Fang M, Xie BB et al (2009) Differentiation of SWO-38 glioma cells induced by CDA-2 is mediated by peroxisome proliferator-activated receptor gamma. J Neurooncol 95:29–36PubMedCrossRef

28.

Xie YK, Huo SF, Zhang G, Zhang F, Lian ZP et al (2012) CDA-2 induces cell differentiation through suppressing Twist/SLUG signaling via miR-124 in glioma. J Neurooncol 110:179–186PubMedCrossRef

29.

Poomsawat S, Buajeeb W, Khovidhunkit SO, Punyasingh J (2010) Alteration in the expression of cdk4 and cdk6 proteins in oral cancer and premalignant lesions. J Oral Pathol Med 39:793–799PubMedCrossRef

30.

Kirsch DG, Doseff A, Chau BN, Lim DS, de Souza-Pinto NC et al (1999) Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c. J Biol Chem 274:21155–21161PubMedCrossRef

31.

Nuovo GJ (2010) In situ detection of microRNAs in paraffin embedded, formalin fixed tissues and the co-localization of their putative targets. Methods 52:307–315PubMedCrossRef

32.

Wu A, Wu B, Guo J, Luo W, Wu D et al (2011) Elevated expression of CDK4 in lung cancer. J Transl Med 9:38PubMedCrossRef

33.

Yaromina A, Krause M, Thames H, Rosner A, Krause M et al (2007) Pre-treatment number of clonogenic cells and their radiosensitivity are major determinants of local tumour control after fractionated irradiation. Radiother Oncol 83:304–310PubMedCrossRef

34.

Ponten J, Westermark B (1978) Properties of human malignant glioma cells in vitro. Med Biol 56:184–193PubMed

35.

Park SH, Cho HN, Lee SJ, Kim TH, Lee Y et al (2000) Hsp25-induced radioresistance is associated with reduction of death by apoptosis: involvement of Bcl2 and the cell cycle. Radiat Res 154:421–428PubMedCrossRef

36.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109PubMedCrossRef

37.

Lindberg D, Hessman O, Akerstrom G, Westin G (2007) Cyclin-dependent kinase 4 (CDK4) expression in pancreatic endocrine tumors. Neuroendocrinology 86:112–118PubMedCrossRef

38.

Dobashi Y, Goto A, Fukayama M, Abe A, Ooi A (2004) Overexpression of cdk4/cyclin D1, a possible mediator of apoptosis and an indicator of prognosis in human primary lung carcinoma. Int J Cancer 110:532–541PubMedCrossRef

39.

Shimura T, Noma N, Oikawa T, Ochiai Y, Kakuda S et al (2012) Activation of the AKT/cyclin D1/Cdk4 survival signaling pathway in radioresistant cancer stem cells. Oncogenesis 1:e12PubMedCrossRef

40.

Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides GA et al (2011) An HNF4alpha-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 147:1233–1247PubMedCrossRef

41.

Chun-Zhi Z, Lei H, An-Ling Z, Yan-Chao F, Xiao Y et al (2010) MicroRNA-221 and microRNA-222 regulate gastric carcinoma cell proliferation and radioresistance by targeting PTEN. BMC Cancer 10:367PubMedCrossRef

42.

Wagner-Ecker M, Schwager C, Wirkner U, Abdollahi A, Huber PE (2010) MicroRNA expression after ionizing radiation in human endothelial cells. Radiat Oncol 5:25PubMedCrossRef

43.

Chistiakov DA, Chekhonin VP (2012) Contribution of microRNAs to radio- and chemoresistance of brain tumors and their therapeutic potential. Eur J Pharmacol 684:8–18PubMedCrossRef

44.

Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK et al (2008) miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 6:14PubMedCrossRef

45.

Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang XF et al (2010) Notch promotes radioresistance of glioma stem cells. Stem Cells 28:17–28PubMedCrossRef

46.

Wei J, Kong L-Y et al (2012) miR-124 as a novel immunotherapeutic molecule to reverse glioma-mediated immune suppression and enhance anti-tumor clearance. Neuro-Oncology 14:44–45

47.

Wang X, Jiang CM, Wan HY, Wu JL, Quan WQ et al (2012) CDA-2, a urinary preparation, inhibits lung cancer development through the suppression of NF-kappaB activation in myeloid cell. PLoS ONE 7:e52117PubMedCrossRef

48.

Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD et al (2009) Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27:2059–2068PubMedCrossRef

49.

Falkvoll KH (1990) The occurrence of apoptosis, abnormal mitoses, cells dying in mitosis and micronuclei in a human melanoma xenograft exposed to single dose irradiation. Strahlenther Onkol 166:487–492PubMed

50.

Radford IR, Murphy TK (1994) Radiation response of mouse lymphoid and myeloid cell lines. Part III. Different signals can lead to apoptosis and may influence sensitivity to killing by DNA double-strand breakage. Int J Radiat Biol 65:229–239PubMedCrossRef

51.

Guo M, Chen C, Vidair C, Marino S, Dewey WC et al (1997) Characterization of radiation-induced apoptosis in rodent cell lines. Radiat Res 147:295–303PubMedCrossRef

52.

Kumala S, Niemiec P, Widel M, Hancock R, Rzeszowska-Wolny J (2003) Apoptosis and clonogenic survival in three tumour cell lines exposed to gamma rays or chemical genotoxic agents. Cell Mol Biol Lett 8:655–665PubMed

53.

Russell J, Ling CC (2003) Studies with cytotoxic agents suggest that apoptosis is not a major determinant of clonogenic death in neuroblastoma cells. Eur J Cancer 39:2234–2238PubMedCrossRef

54.

Lo Nigro C, Arnolfo E, Taricco E, Fruttero A, Russi EG et al (2007) The cisplatin-irradiation combination suggests that apoptosis is not a major determinant of clonogenic death. Anticancer Drugs 18:659–667PubMedCrossRef

Title: miR-124 radiosensitizes human glioma cells by targeting CDK4
Authors: Xubin Deng
Lei Ma
Minhua Wu
Gong Zhang
Chuan Jin
Yuping Guo
Ruilei Liu
Publication date: 01-09-2013
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 3/2013
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-013-1179-2

At a glance: The STEP trials

Springer Medicine

miR-124 radiosensitizes human glioma cells by targeting CDK4

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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