Overexpression of EPAC2 Reduces the Invasion of Glioma Cells Via MMP-2

Overview

Journal Oncol Lett

Specialty Oncology

Date 2019 Jun 13

PMID 31186720

Citations 3

Authors

Ming Jiang

Yan Zhuang

Wang-Cun Zu

Lei Jiao

Seidu A Richard

Shiming Zhang

Affiliations

Soon will be listed here.

Abstract

Exchange proteins directly activated by cAMP (EPACs) are crucial cyclic adenosine 3',5'-monophosphate- determined signaling pathway intercessors, which are associated with the pathogenesis of neurological disorders and numerous human diseases. To the best of our knowledge, the role of EPAC2 signaling via matrix metalloproteinase 2 (MMP-2) in the pathogenesis of glioma has not been studied. Therefore, the present study focused on the role of EPAC2 in glioma, and assessed the invasiveness of human glioma cell lines following EPAC2 overexpression. Expression levels of EPAC2 in normal brain tissues and clinical glioma specimens were detected by western blotting. An EPAC2 overexpression vector was transfected into U251 and U87 cell lines to increase the expression levels of EPAC2. Expression levels of MMP-2 were detected by western blotting, and the invasive abilities of glioma cells were detected by a Transwell assay. EPAC2 was relatively highly expressed in normal brain tissue, while EPAC2 expression was significantly decreased in clinical glioma specimens (P<0.01). transfection of EPAC2 overexpression vector significantly reduced the MMP-2 protein levels of glioma cells, and, at the same time, the invasive cell number was significantly decreased in a Transwell assay. The present study demonstrated that MMP-2 regulation via EPAC2 overexpression is a novel promising therapeutic route in malignant types of glioma.

Citing Articles

The Pivotal Immunomodulatory and Anti-Inflammatory Effect of Histone-Lysine N-Methyltransferase in the Glioma Microenvironment: Its Biomarker and Therapy Potentials.

Richard S, Eugene K Anal Cell Pathol (Amst). 2021; 2021:4907167.

PMID: 34745848 PMC: 8566080. DOI: 10.1155/2021/4907167.

C3G Protein, a New Player in Glioblastoma.

Manzano S, Gutierrez-Uzquiza A, Bragado P, Cuesta A, Guerrero C, Porras A Int J Mol Sci. 2021; 22(18).

PMID: 34576182 PMC: 8466177. DOI: 10.3390/ijms221810018.

EPAC2: A new and promising protein for glioma pathogenesis and therapy.

Richard S Oncol Rev. 2020; 14(1):446.

PMID: 32395202 PMC: 7204831. DOI: 10.4081/oncol.2020.446.

References

Forsyth P, Wong H, Laing T, Rewcastle N, Morris D, Muzik H . Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas. Br J Cancer. 1999; 79(11-12):1828-35. PMC: 2362801. DOI: 10.1038/sj.bjc.6690291. View

Wang M, Wang T, Liu S, Yoshida D, Teramoto A . The expression of matrix metalloproteinase-2 and -9 in human gliomas of different pathological grades. Brain Tumor Pathol. 2004; 20(2):65-72. DOI: 10.1007/BF02483449. View

Guo P, Imanishi Y, Cackowski F, Jarzynka M, Tao H, Nishikawa R . Up-regulation of angiopoietin-2, matrix metalloprotease-2, membrane type 1 metalloprotease, and laminin 5 gamma 2 correlates with the invasiveness of human glioma. Am J Pathol. 2005; 166(3):877-90. PMC: 1602359. DOI: 10.1016/s0002-9440(10)62308-5. View

Zhou Y, Hess K, Liu L, Linskey M, Yung W . Modeling prognosis for patients with malignant astrocytic gliomas: quantifying the expression of multiple genetic markers and clinical variables. Neuro Oncol. 2005; 7(4):485-94. PMC: 1871729. DOI: 10.1215/S1152851704000730. View

Bos J . Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci. 2006; 31(12):680-6. DOI: 10.1016/j.tibs.2006.10.002. View

Du R, Petritsch C, Lu K, Liu P, Haller A, Ganss R . Matrix metalloproteinase-2 regulates vascular patterning and growth affecting tumor cell survival and invasion in GBM. Neuro Oncol. 2008; 10(3):254-64. PMC: 2563048. DOI: 10.1215/15228517-2008-001. View

Cebolla B, Fernandez-Perez A, Perea G, Araque A, Vallejo M . DREAM mediates cAMP-dependent, Ca2+-induced stimulation of GFAP gene expression and regulates cortical astrogliogenesis. J Neurosci. 2008; 28(26):6703-13. PMC: 6670409. DOI: 10.1523/JNEUROSCI.0215-08.2008. View

Wang D, Bordey A . The astrocyte odyssey. Prog Neurobiol. 2008; 86(4):342-67. PMC: 2613184. DOI: 10.1016/j.pneurobio.2008.09.015. View

Vallejo M . PACAP signaling to DREAM: a cAMP-dependent pathway that regulates cortical astrogliogenesis. Mol Neurobiol. 2009; 39(2):90-100. DOI: 10.1007/s12035-009-8055-2. View

10.

Malchinkhuu E, Sato K, Maehama T, Ishiuchi S, Yoshimoto Y, Mogi C . Role of Rap1B and tumor suppressor PTEN in the negative regulation of lysophosphatidic acid--induced migration by isoproterenol in glioma cells. Mol Biol Cell. 2009; 20(24):5156-65. PMC: 2793292. DOI: 10.1091/mbc.e09-08-0692. View

11.

Grandoch M, Roscioni S, Schmidt M . The role of Epac proteins, novel cAMP mediators, in the regulation of immune, lung and neuronal function. Br J Pharmacol. 2009; 159(2):265-84. PMC: 2825350. DOI: 10.1111/j.1476-5381.2009.00458.x. View

12.

Gloerich M, Bos J . Epac: defining a new mechanism for cAMP action. Annu Rev Pharmacol Toxicol. 2010; 50:355-75. DOI: 10.1146/annurev.pharmtox.010909.105714. View

13.

Short S, Giampieri S, Worku M, Alcaide-German M, Sioftanos G, Bourne S . Rad51 inhibition is an effective means of targeting DNA repair in glioma models and CD133+ tumor-derived cells. Neuro Oncol. 2011; 13(5):487-99. PMC: 3093331. DOI: 10.1093/neuonc/nor010. View

14.

He J, Shan Z, Li L, Liu F, Liu Z, Song M . Expression of glioma stem cell marker CD133 and O6-methylguanine-DNA methyltransferase is associated with resistance to radiotherapy in gliomas. Oncol Rep. 2011; 26(5):1305-13. DOI: 10.3892/or.2011.1393. View

15.

Sugimoto N, Miwa S, Tsuchiya H, Hitomi Y, Nakamura H, Yachie A . Targeted activation of PKA and Epac promotes glioblastoma regression . Mol Clin Oncol. 2014; 1(2):281-285. PMC: 3915280. DOI: 10.3892/mco.2013.65. View

16.

Mostafavi H, Khaksarian M, Joghataei M, Soleimani M, Hassanzadeh G, Eftekhari S . Selective β2 adrenergic agonist increases Cx43 and miR-451 expression via cAMP-Epac. Mol Med Rep. 2014; 9(6):2405-10. DOI: 10.3892/mmr.2014.2120. View

17.

Osman M . Phase II trial of temozolomide and reirradiation using conformal 3D-radiotherapy in recurrent brain gliomas. Ann Transl Med. 2014; 2(5):44. PMC: 4200682. DOI: 10.3978/j.issn.2305-5839.2014.05.06. View

18.

Fernandes H, Riordan S, Nomura T, Remmers C, Kraniotis S, Marshall J . Epac2 Mediates cAMP-Dependent Potentiation of Neurotransmission in the Hippocampus. J Neurosci. 2015; 35(16):6544-53. PMC: 4405561. DOI: 10.1523/JNEUROSCI.0314-14.2015. View

19.

Lee K, Kobayashi Y, Seo H, Kwak J, Masuda A, Lim C . Involvement of cAMP-guanine nucleotide exchange factor II in hippocampal long-term depression and behavioral flexibility. Mol Brain. 2015; 8:38. PMC: 4477293. DOI: 10.1186/s13041-015-0130-1. View

20.

Sugawara K, Shibasaki T, Takahashi H, Seino S . Structure and functional roles of Epac2 (Rapgef4). Gene. 2015; 575(2 Pt 3):577-83. PMC: 6636354. DOI: 10.1016/j.gene.2015.09.029. View