MicroRNA-34a Inhibits Glioblastoma Growth by Targeting Multiple Oncogenes

Overview

Journal Cancer Res

Specialty Oncology

Date 2009 Sep 24

PMID 19773441

Citations 310

Authors

Yunqing Li

Fadila Guessous

Ying Zhang

Charles diPierro

Benjamin Kefas

Elizabeth Johnson

Lukasz Marcinkiewicz

Jinmai Jiang

Yanzhi Yang

Thomas D Schmittgen

Beatriz Lopes

David Schiff

Benjamin Purow

Roger Abounader

Affiliations

Soon will be listed here.

Abstract

MicroRNA-34a (miR-34a) is a transcriptional target of p53 that is down-regulated in some cancer cell lines. We studied the expression, targets, and functional effects of miR-34a in brain tumor cells and human gliomas. Transfection of miR-34a down-regulated c-Met in human glioma and medulloblastoma cells and Notch-1, Notch-2, and CDK6 protein expressions in glioma cells. miR-34a expression inhibited c-Met reporter activities in glioma and medulloblastoma cells and Notch-1 and Notch-2 3'-untranslated region reporter activities in glioma cells and stem cells. Analysis of human specimens showed that miR-34a expression is down-regulated in glioblastoma tissues as compared with normal brain and in mutant p53 gliomas as compared with wild-type p53 gliomas. miR-34a levels in human gliomas inversely correlated to c-Met levels measured in the same tumors. Transient transfection of miR-34a into glioma and medulloblastoma cell lines strongly inhibited cell proliferation, cell cycle progression, cell survival, and cell invasion, but transfection of miR-34a into human astrocytes did not affect cell survival and cell cycle status. Forced expression of c-Met or Notch-1/Notch-2 transcripts lacking the 3'-untranslated region sequences partially reversed the effects of miR-34a on cell cycle arrest and cell death in glioma cells and stem cells, respectively. Also, transient expression of miR-34a in glioblastoma cells strongly inhibited in vivo glioma xenograft growth. Together, these findings represent the first comprehensive analysis of the role of miR-34a in gliomas. They show that miR-34a suppresses brain tumor growth by targeting c-Met and Notch. The results also suggest that miR-34a could serve as a potential therapeutic agent for brain tumors.

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References

Kanamori M, Kawaguchi T, Nigro J, Feuerstein B, Berger M, Miele L . Contribution of Notch signaling activation to human glioblastoma multiforme. J Neurosurg. 2007; 106(3):417-27. DOI: 10.3171/jns.2007.106.3.417. View

Abounader R, Ranganathan S, Lal B, Fielding K, Book A, Dietz H . Reversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte growth factor and c-met expression. J Natl Cancer Inst. 1999; 91(18):1548-56. DOI: 10.1093/jnci/91.18.1548. View

Sun F, Fu H, Liu Q, Tie Y, Zhu J, Xing R . Downregulation of CCND1 and CDK6 by miR-34a induces cell cycle arrest. FEBS Lett. 2008; 582(10):1564-8. DOI: 10.1016/j.febslet.2008.03.057. View

Abounader R, Laterra J . Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro Oncol. 2005; 7(4):436-51. PMC: 1871724. DOI: 10.1215/S1152851705000050. View

Shih A, Holland E . Notch signaling enhances nestin expression in gliomas. Neoplasia. 2007; 8(12):1072-82. PMC: 1790729. DOI: 10.1593/neo.06526. View

Purow B, Sundaresan T, Burdick M, Kefas B, Comeau L, Hawkinson M . Notch-1 regulates transcription of the epidermal growth factor receptor through p53. Carcinogenesis. 2008; 29(5):918-25. PMC: 2902388. DOI: 10.1093/carcin/bgn079. View

Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N . Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell. 2007; 26(5):731-43. DOI: 10.1016/j.molcel.2007.05.017. View

Purow B, Haque R, Noel M, Su Q, Burdick M, Lee J . Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 2005; 65(6):2353-63. DOI: 10.1158/0008-5472.CAN-04-1890. View

Caldas C, Brenton J . Sizing up miRNAs as cancer genes. Nat Med. 2005; 11(7):712-4. DOI: 10.1038/nm0705-712. View

10.

Li Y, Lal B, Kwon S, Fan X, Saldanha U, Reznik T . The scatter factor/hepatocyte growth factor: c-met pathway in human embryonal central nervous system tumor malignancy. Cancer Res. 2005; 65(20):9355-62. DOI: 10.1158/0008-5472.CAN-05-1946. View

11.

Mendrzyk F, Radlwimmer B, Joos S, Kokocinski F, Benner A, Stange D . Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma. J Clin Oncol. 2005; 23(34):8853-62. DOI: 10.1200/JCO.2005.02.8589. View

12.

He L, He X, Lim L, de Stanchina E, Xuan Z, Liang Y . A microRNA component of the p53 tumour suppressor network. Nature. 2007; 447(7148):1130-4. PMC: 4590999. DOI: 10.1038/nature05939. View

13.

Rosen E, Laterra J, Joseph A, Jin L, Fuchs A, Way D . Scatter factor expression and regulation in human glial tumors. Int J Cancer. 1996; 67(2):248-55. DOI: 10.1002/(SICI)1097-0215(19960717)67:2<248::AID-IJC16>3.0.CO;2-7. View

14.

Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Korner H . Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle. 2008; 7(16):2591-600. DOI: 10.4161/cc.7.16.6533. View

15.

Barbashina V, Salazar P, Holland E, Rosenblum M, Ladanyi M . Allelic losses at 1p36 and 19q13 in gliomas: correlation with histologic classification, definition of a 150-kb minimal deleted region on 1p36, and evaluation of CAMTA1 as a candidate tumor suppressor gene. Clin Cancer Res. 2005; 11(3):1119-28. View

16.

Yan D, Zhou X, Chen X, Hu D, Dong X, Wang J . MicroRNA-34a inhibits uveal melanoma cell proliferation and migration through downregulation of c-Met. Invest Ophthalmol Vis Sci. 2008; 50(4):1559-65. DOI: 10.1167/iovs.08-2681. View

17.

Pillai R, Bhattacharyya S, Filipowicz W . Repression of protein synthesis by miRNAs: how many mechanisms?. Trends Cell Biol. 2007; 17(3):118-26. DOI: 10.1016/j.tcb.2006.12.007. View

18.

Li Y, Guessous F, Kwon S, Kumar M, Ibidapo O, Fuller L . PTEN has tumor-promoting properties in the setting of gain-of-function p53 mutations. Cancer Res. 2008; 68(6):1723-31. PMC: 3813002. DOI: 10.1158/0008-5472.CAN-07-1963. View

19.

Moriyama T, Kataoka H, Kawano H, Yokogami K, Nakano S, Goya T . Comparative analysis of expression of hepatocyte growth factor and its receptor, c-met, in gliomas, meningiomas and schwannomas in humans. Cancer Lett. 1998; 124(2):149-55. DOI: 10.1016/s0304-3835(97)00469-2. View

20.

Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li Y . Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 2006; 66(15):7445-52. DOI: 10.1158/0008-5472.CAN-06-0858. View