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Cancer Cell International
Published in: Cancer Cell International 1/2013

Open Access 01-12-2013 | Primary research

MiR-99a may serve as a potential oncogene in pediatric myeloid leukemia

Authors: Lidan Zhang, Xiaojuan Li, Zhiyong Ke, Libin Huang, Yanni Liang, Jun Wu, Xiaoli Zhang, Yueqin Chen, Hua Zhang, Xuequn Luo

Published in: Cancer Cell International | Issue 1/2013

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Abstract

Background

Leukemia is the most common malignant proliferative disease in children. Our previous study found that miR-99a was up-regulated in pediatric primary AML using microRNA expression profiles. Up to date, although there is a certain number of reports on microRNA expression features and functions in pediatric acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), the expression and function of miR-99a in these diseases remain to be investigated.

Methods

qRT-PCR was performed to measure the expression level of miR-99a in 88 samples including 68 pediatric acute myeloid leukemia patients, 8 chronic myeloid leukemia patients and 12 pediatric controls. MTT assay, apoptosis assay, dual-luciferase reporter transfection assay and western blot analysis were used to investigate the function of miR-99a.

Results

MiR-99a was highly expressed in pediatric-onset AML (M1-M5) and CML, while significantly lowly expressed during complete remission of these diseases. MTT assay indicated that the proliferations of K562 and HL60 cells were significantly promoted by miR-99a, and apoptosis assessment by Annexin V/propidium iodide staining demonstrated that the apoptosis of these cells was inhibited by miR-99a. Additionally, dual-luciferase reporter transfection assay and western blot analysis indicated that miR-99a may target CTDSPL and TRIB2, which are two tumor suppressor genes.

Conclusions

This study revealed that miR-99a may play a potential oncogenic role in pediatric myeloid leukemia including AML and CML via regulating tumor suppressors CTDSPL and TRIB2, suggesting that these two leukemias might share some common biological pathways involved in the generation and development of disease and miR-99a could be a common therapeutic target for myeloid leukemias treatment.
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Literature
1.
Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004, 116: 281-297. 10.1016/S0092-8674(04)00045-5.CrossRefPubMed
2.
Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM: Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005, 433: 769-773. 10.1038/nature03315.CrossRefPubMed
3.
4.
Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA. 2004, 101: 2999-3004. 10.1073/pnas.0307323101.PubMedCentralCrossRefPubMed
5.
Chen CZ: MicroRNAs as oncogenes and tumor suppressors. N Engl J Med. 2005, 353: 1768-1771. 10.1056/NEJMp058190.CrossRefPubMed
6.
Carlsson J, Davidsson S, Helenius G, Karlsson M, Lubovac Z, Andrén O, Olsson B, Klinga-Levan K: A miRNA expression signature that separates between normal and malignant prostate tissues. Cancer Cell Int. 2011, 11: 14-10.1186/1475-2867-11-14.PubMedCentralCrossRefPubMed
7.
Garzon R, Volinia S, Liu CG, Fernandez-Cymering C, Palumbo T, Pichiorri F, Fabbri M, Coombes K, Alder H, Nakamura T, Flomenberg N, Marcucci G, Calin GA, Kornblau SM, Kantarjian H, Bloomfield CD, Andreeff M, Croce CM: MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood. 2008, 111: 3183-3189. 10.1182/blood-2007-07-098749.PubMedCentralCrossRefPubMed
8.
Gimenes-Teixeira HL, Lucena-Araujo AR, Dos Santos GA, Zanette DL, Scheucher PS, Oliveira LC, Dalmazzo LF, Silva-Júnior WA, Falcão RP, Rego EM: Increased expression of miR-221 is associated with shorter overall survival in T-cell acute lymphoid leukemia. Exp Hematol Oncol. 2013, 2: 10-10.1186/2162-3619-2-10.PubMedCentralCrossRefPubMed
9.
Schwind S, Marcucci G, Maharry K, Radmacher MD, Mrózek K, Holland KB, Margeson D, Becker H, Whitman SP, Wu YZ, Metzeler KH, Powell BL, Kolitz JE, Carter TH, Moore JO, Baer MR, Carroll AJ, Caligiuri MA, Larson RA, Bloomfield CD: BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood. 2010, 116: 5660-5669. 10.1182/blood-2010-06-290536.PubMedCentralCrossRefPubMed
10.
Labbaye C, Testa U: The emerging role of MIR-146A in the control of hematopoiesis, immune function and cancer. J Hematol Oncol. 2012, 5: 13-10.1186/1756-8722-5-13.PubMedCentralCrossRefPubMed
11.
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM: Frequent deletions and down -regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002, 99: 15524-15529. 10.1073/pnas.242606799.PubMedCentralCrossRefPubMed
12.
Han YC, Park CY, Bhagat G, Zhang J, Wang Y, Fan JB, Liu M, Zou Y, Weissman IL, Gu H: MicroRNA-29a induces aberrant self-renewal capacity in hematopoietic progenitors, biased myeloid development, and acute myeloid leukemia. J Exp Med. 2010, 207: 475-489. 10.1084/jem.20090831.PubMedCentralCrossRefPubMed
13.
Faraoni I, Laterza S, Ardiri D, Ciardi C, Fazi F, Lo-Coco F: MiR-424 and miR-155 deregulated expression in cytogenetically normal acute myeloid leukaemia: correlation with NPM1 and FLT3 mutation status. J Hematol Oncol. 2012, 5: 26-10.1186/1756-8722-5-26.PubMedCentralCrossRefPubMed
14.
Zhang H, Luo XQ, Zhang P, Huang LB, Zheng YS, Wu J, Zhou H, Qu LH, Xu L, Chen YQ: MicroRNA Patterns Associated with Clinical Prognostic Parameters and CNS Relapse Prediction in Pediatric Acute Leukemia. Plos One. 2009, 4: e7826-10.1371/journal.pone.0007826.PubMedCentralCrossRefPubMed
15.
Kashuba VI, Li J, Wang F, Senchenko VN, Protopopov A, Malyukova A, Kutsenko AS, Kadyrova E, Zabarovska VI, Muravenko OV, Zelenin AV, Kisselev LL, Kuzmin I, Minna JD, Winberg G, Ernberg I, Braga E, Lerman MI, Klein G, Zabarovsky ER: RBSP3 (HYA22) is a tumor suppressor gene implicated in major epithelial malignancies. Proc Natl Acad Sci USA. 2004, 101: 4906-4911. 10.1073/pnas.0401238101.PubMedCentralCrossRefPubMed
16.
Zheng YS, Zhang H, Zhang XJ, Feng DD, Luo XQ, Zeng CW, Lin KY, Zhou H, Qu LH, Zhang P, Chen YQ: MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia. Oncogene. 2012, 31: 80-92. 10.1038/onc.2011.208.PubMedCentralCrossRefPubMed
17.
Kashuba VI, Pavlova TV, Grigorieva EV, Kutsenko A, Yenamandra SP, Li J, Wang F, Protopopov AI, Zabarovska VI, Senchenko V, Haraldson K, Eshchenko T, Kobliakova J, Vorontsova O, Kuzmin I, Braga E, Blinov VM, Kisselev LL, Zeng YX, Ernberg I, Lerman MI, Klein G, Zabarovsky ER: High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer. PLoS One. 2009, 4: e5231-10.1371/journal.pone.0005231.PubMedCentralCrossRefPubMed
18.
19.
Hayashita Y: A polycistronic microRNA cluster, miR-17-92, is over-expressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005, 65: 9628-9632. 10.1158/0008-5472.CAN-05-2352.CrossRefPubMed
20.
Schrappe M, Camitta B, Pui CH, Eden T, Gaynon P, Gustafsson G, Janka-Schaub GE, Kamps W, Masera G, Sallan S, Tsuchida M, Vilmer E: Long-term results of large prospective trials in childhood acute lymphoblastic leukaemia. Leukaemia. 2000, 14: 2193-2194. 10.1038/sj.leu.2401977.CrossRef
21.
Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD, Henze G, Gadner H, Odenwald E, Riehm H: Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Munster. Leukaemia. 2000, 12: 2205-2222.CrossRef
22.
Creutzig U, Büchner T, Sauerland MC, Zimmermann M, Reinhardt D, Döhner H, Schlenk RF: Significance of age in acute myeloid leukemia patients younger than 30 years: a common analysis of the pediatric trials AML-BFM 93/98 and the adult trials AMLCG 92/99 and AMLSG HD93/98A. Cancer. 2008, 112: 562-571. 10.1002/cncr.23220.CrossRefPubMed
23.
Breccia M, Alimena G: How to treat CML patients in the tyrosine kinase inhibitors era? From imatinib standard dose to second generation drugs front-line: unmet needs, pitfalls and advantages. Cancer Lett. 2012, 322: 127-132. 10.1016/j.canlet.2012.03.021.CrossRefPubMed
24.
Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM: A MiRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 2005, 353: 1793-1801. 10.1056/NEJMoa050995.CrossRefPubMed
25.
26.
Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM: miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA. 2005, 102: 13944-13949. 10.1073/pnas.0506654102.PubMedCentralCrossRefPubMed
27.
Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C, Bozzoni I: A minicircuitry comprised of miRNA-223 and transcription factors NFI-A and C/EBP alpha regulates human granulopoiesis. Cell. 2005, 123: 819-831. 10.1016/j.cell.2005.09.023.CrossRefPubMed
28.
Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR: MiRNA expression profiles classify human cancer. Nature. 2005, 435: 834-838. 10.1038/nature03702.CrossRefPubMed
29.
Shu J, Jelinek J, Chang H, Shen L, Qin T, Chung W, Oki Y, Issa JP: Silencing of bidirectional promoters by DNA methylation in tumorigenesis. Cancer Res. 2006, 66: 5077-5084. 10.1158/0008-5472.CAN-05-2629.CrossRefPubMed
30.
Ghosh A, Ghosh S, Maiti GP, Sabbir MG, Zabarovsky ER, Roy A, Roychoudhury S, Panda CK: Frequent alterations of the candidate genes hMLH1, ITGA9 and RBSP3 in early dysplastic lesions of head and neck: clinical and prognostic significance. Cancer Sci. 2010, 101: 1511-1520. 10.1111/j.1349-7006.2010.01551.x.CrossRefPubMed
31.
Keeshan K, Bailis W, Dedhia PH, Vega ME, Shestova O, Xu L, Toscano K, Uljon SN, Blacklow SC, Pear WS: Transformation by Tribbles homolog 2 (Trib2) requires both the Trib2 kinase domain and COP1 binding. Blood. 2010, 116: 4948-4957. 10.1182/blood-2009-10-247361.PubMedCentralCrossRefPubMed
32.
Keeshan K, He Y, Wouters BJ, Shestova O, Xu L, Sai H, Rodriguez CG, Maillard I, Tobias JW, Valk P, Carroll M, Aster JC, Delwel R, Pear WS: Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia. Cancer Cell. 2006, 10: 401-411. 10.1016/j.ccr.2006.09.012.PubMedCentralCrossRefPubMed
33.
Keeshan K, Shestova O, Ussin L, Pear WS: Tribbles homolog 2 (Trib2) and HoxA9 cooperate to accelerate acute myelogenous leukemia. Blood Cells Mol Dis. 2008, 40: 119-121. 10.1016/j.bcmd.2007.06.005.CrossRefPubMed
34.
Nagel S, Venturini L, Przybylski GK, Grabarczyk P, Schneider B, Meyer C, Kaufmann M, Schmidt CA, Scherr M, Drexler HG, Macleod RA: Activation of Paired-homeobox gene PITX1 by del(5)(q31) in T-cell acute lymphoblastic leukemia. Leuk Lymphoma. 2011, 52: 1348-1359. 10.3109/10428194.2011.566391.CrossRefPubMed
35.
Cheng AM, Byrom MW, Shelton J, Ford LP: Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 2005, 33: 1290-1297. 10.1093/nar/gki200.PubMedCentralCrossRefPubMed
36.
Gilby DC, Sung HY, Winship PR, Goodeve AC, Reilly JT, Kiss-Toth E: Tribbles-1 and -2 are tumour suppressors, down-regulated in human acute myeloid leukaemia. Immunol Lett. 2010, 130: 115-124. 10.1016/j.imlet.2009.12.007.CrossRefPubMed
37.
Wong TS, Liu XB, Wong BY, Ng RW, Yuen AP, Wei WI: Mature miR-184 as Potential Oncogenic microRNA of Squamous Cell Carcinoma of Tongue. Clin Cancer Res. 2008, 14: 2588-2592. 10.1158/1078-0432.CCR-07-0666.CrossRefPubMed
38.
Wszolek MF, Rieger-Christ KM, Kenney PA, Gould JJ, Silva Neto B, Lavoie AK, Logvinenko T, Libertino JA, Summerhayes IC: A MicroRNA expression profile defining the invasive bladder tumor phenotype. Urol Oncol. 2009, 26: 2301-2306.
39.
Yamada H, Yanagisawa K, Tokumaru S, Taguchi A, Nimura Y, Osada H, Nagino M, Takahashi T: Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at 21q11-21 in human lung cancer. Genes Chromosomes Cancer. 2008, 47: 810-818. 10.1002/gcc.20582.CrossRefPubMed
40.
Calin GA, Liu CG, Sevignani C, Ferracin M, Felli N, Dumitru CD, Shimizu M, Cimmino A, Zupo S, Dono M, Dell'Aquila ML, Alder H, Rassenti L, Kipps TJ, Bullrich F, Negrini M, Croce CM: MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukaemias. Proc Natl Acad Sci USA. 2004, 101: 11755-11760. 10.1073/pnas.0404432101.PubMedCentralCrossRefPubMed
41.
Shao Y, Qu Y, Dang S, Yao B, Ji M: MiR-145 inhibits oral squamous cell carcinoma (OSCC) cell growth by targeting c-Myc and Cdk6. Cancer Cell Int. 2013, 13: 51-10.1186/1475-2867-13-51.PubMedCentralCrossRefPubMed
42.
Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM: A microRNA expression signature of human solid tumours defines cancer gene targets. Proc Natl Acad Sci USA. 2006, 103: 2257-2261. 10.1073/pnas.0510565103.PubMedCentralCrossRefPubMed
43.
Yu Z, Wang C, Wang M, Li Z, Casimiro MC, Liu M, Wu K, Whittle J, Ju X, Hyslop T, McCue P, Pestell RG: A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation. J Cell Biol. 2008, 182: 509-517. 10.1083/jcb.200801079.PubMedCentralCrossRefPubMed
44.
Krek A, Grün D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M, Rajewsky N: Combinatorial microRNA target predictions. Nat Genet. 2005, 37: 495-500. 10.1038/ng1536.CrossRefPubMed
45.
Xie X, Lu J, Kulbokas EJ, Golub TR, Mootha V, Lindblad-Toh K, Lander ES, Kellis M: Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals. Nature. 2005, 434: 338-345. 10.1038/nature03441.PubMedCentralCrossRefPubMed
Metadata
Title
MiR-99a may serve as a potential oncogene in pediatric myeloid leukemia
Authors
Lidan Zhang
Xiaojuan Li
Zhiyong Ke
Libin Huang
Yanni Liang
Jun Wu
Xiaoli Zhang
Yueqin Chen
Hua Zhang
Xuequn Luo
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2013
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/1475-2867-13-110

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