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Published in: Journal of Cancer Research and Clinical Oncology 12/2011

01-12-2011 | Original Paper

RUNX3 expression is lost in glioma and its restoration causes drastic suppression of tumor invasion and migration

Authors: Peng-Jin Mei, Jin Bai, Hui Liu, Chen Li, Yong-Ping Wu, Zheng-Quan Yu, Jun-Nian Zheng

Published in: Journal of Cancer Research and Clinical Oncology | Issue 12/2011

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Abstract

Purpose

The aim of this study is to investigate whether the expression of RUNX3 is related to the development of glioma, and the role of RUNX3 in glioma cells growth, invasion and migration.

Methods

We analyzed the protein expression of RUNX3 by immunohistochemistry in 188 glioma tissues, 8 normal brain tissues and 8 tumor adjacent normal brain tissues using tissue microarray technique. We studied whether RUNX3 restoration can suppress glioma cells growth, invasion and migration by performing MTT cell proliferation assay, matrigel cell invasion assay, wound-healing assay and migration assay. We also detected MMP-2 protein expression and enzyme activity by western blot analysis and gelatin zymography.

Results

We found that RUNX3 expression was decreased in benign tumor and malignant tumor compared with tumor adjacent normal brain tissue (P < 0.01 and P < 0.05, respectively). We did not find any correlation between RUNX3 expression and clinicopathological parameters. In addition, we demonstrated that re-expression of RUNX3 in glioma cells resulted in significantly inhibited cell invasion and migration abilities. This reduced cell invasion and migration abilities were due to MMP-2 protein expression and enzyme activity suppression after RUNX3 restoration.

Conclusions

Our data indicated that RUNX3 expression is significantly decreased in human glioma, and targeting of the RUNX3 pathway may constitute a potential treatment modality for glioma.
Literature
go back to reference Ahlquist T, Lind GE, Costa VL, Meling GI, Vatn M, Hoff GS, Rognum TO, Skotheim RI, Thiis-Evensen E, Lothe RA (2008) Gene methylation profiles of normal mucosa, and benign and malignant colorectal tumors identify early onset markers. Mol Cancer 7:94. doi:10.1186/1476-4598-7-94 PubMedCrossRef Ahlquist T, Lind GE, Costa VL, Meling GI, Vatn M, Hoff GS, Rognum TO, Skotheim RI, Thiis-Evensen E, Lothe RA (2008) Gene methylation profiles of normal mucosa, and benign and malignant colorectal tumors identify early onset markers. Mol Cancer 7:94. doi:10.​1186/​1476-4598-7-94 PubMedCrossRef
go back to reference Bae SC, Takahashi E, Zhang YW, Ogawa E, Shigesada K, Namba Y, Satake M, Ito Y (1995) Cloning, mapping and expression of PEBP2 alpha C, a third gene encoding the mammalian runt domain. Gene 159(2):245–248PubMedCrossRef Bae SC, Takahashi E, Zhang YW, Ogawa E, Shigesada K, Namba Y, Satake M, Ito Y (1995) Cloning, mapping and expression of PEBP2 alpha C, a third gene encoding the mammalian runt domain. Gene 159(2):245–248PubMedCrossRef
go back to reference Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG, Quigley JP, Cheresh DA (1996) Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 85(5):683–693PubMedCrossRef Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG, Quigley JP, Cheresh DA (1996) Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 85(5):683–693PubMedCrossRef
go back to reference Cha HJ, Bae SK, Lee HY, Lee OH, Sato H, Seiki M, Park BC, Kim KW (1996) Anti-invasive activity of ursolic acid correlates with the reduced expression of matrix metalloproteinase-9 (MMP-9) in HT1080 human fibrosarcoma cells. Cancer Res 56(10):2281–2284PubMed Cha HJ, Bae SK, Lee HY, Lee OH, Sato H, Seiki M, Park BC, Kim KW (1996) Anti-invasive activity of ursolic acid correlates with the reduced expression of matrix metalloproteinase-9 (MMP-9) in HT1080 human fibrosarcoma cells. Cancer Res 56(10):2281–2284PubMed
go back to reference Guan H, Cai J, Zhang N, Wu J, Yuan J, Li J, Li M (2011) Sp1 is upregulated in human glioma, promotes MMP-2-mediated cell invasion and predicts poor clinical outcome. Int J Cancer. doi:10.1002/ijc.26049 Guan H, Cai J, Zhang N, Wu J, Yuan J, Li J, Li M (2011) Sp1 is upregulated in human glioma, promotes MMP-2-mediated cell invasion and predicts poor clinical outcome. Int J Cancer. doi:10.​1002/​ijc.​26049
go back to reference Ichimura K, Vogazianou AP, Liu L, Pearson DM, Backlund LM, Plant K, Baird K, Langford CF, Gregory SG, Collins VP (2008) 1p36 is a preferential target of chromosome 1 deletions in astrocytic tumours and homozygously deleted in a subset of glioblastomas. Oncogene 27(14):2097–2108. doi:10.1038/sj.onc.1210848 PubMedCrossRef Ichimura K, Vogazianou AP, Liu L, Pearson DM, Backlund LM, Plant K, Baird K, Langford CF, Gregory SG, Collins VP (2008) 1p36 is a preferential target of chromosome 1 deletions in astrocytic tumours and homozygously deleted in a subset of glioblastomas. Oncogene 27(14):2097–2108. doi:10.​1038/​sj.​onc.​1210848 PubMedCrossRef
go back to reference Javed A, Barnes GL, Pratap J, Antkowiak T, Gerstenfeld LC, van Wijnen AJ, Stein JL, Lian JB, Stein GS (2005) Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo. Proc Natl Acad Sci USA 102(5):1454–1459. doi:10.1073/pnas.0409121102 PubMedCrossRef Javed A, Barnes GL, Pratap J, Antkowiak T, Gerstenfeld LC, van Wijnen AJ, Stein JL, Lian JB, Stein GS (2005) Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo. Proc Natl Acad Sci USA 102(5):1454–1459. doi:10.​1073/​pnas.​0409121102 PubMedCrossRef
go back to reference Lau QC, Raja E, Salto-Tellez M, Liu Q, Ito K, Inoue M, Putti TC, Loh M, Ko TK, Huang C, Bhalla KN, Zhu T, Ito Y, Sukumar S (2006) RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer. Cancer Res 66(13):6512–6520. doi:10.1158/0008-5472.CAN-06-0369 PubMedCrossRef Lau QC, Raja E, Salto-Tellez M, Liu Q, Ito K, Inoue M, Putti TC, Loh M, Ko TK, Huang C, Bhalla KN, Zhu T, Ito Y, Sukumar S (2006) RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer. Cancer Res 66(13):6512–6520. doi:10.​1158/​0008-5472.​CAN-06-0369 PubMedCrossRef
go back to reference Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ, Lee KY, Nomura S, Lee CW, Han SB, Kim HM, Kim WJ, Yamamoto H, Yamashita N, Yano T, Ikeda T, Itohara S, Inazawa J, Abe T, Hagiwara A, Yamagishi H, Ooe A, Kaneda A, Sugimura T, Ushijima T, Bae SC, Ito Y (2002) Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109(1):113–124PubMedCrossRef Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ, Lee KY, Nomura S, Lee CW, Han SB, Kim HM, Kim WJ, Yamamoto H, Yamashita N, Yano T, Ikeda T, Itohara S, Inazawa J, Abe T, Hagiwara A, Yamagishi H, Ooe A, Kaneda A, Sugimura T, Ushijima T, Bae SC, Ito Y (2002) Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109(1):113–124PubMedCrossRef
go back to reference Roberts AB, Anzano MA, Wakefield LM, Roche NS, Stern DF, Sporn MB (1985) Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci USA 82(1):119–123PubMedCrossRef Roberts AB, Anzano MA, Wakefield LM, Roche NS, Stern DF, Sporn MB (1985) Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci USA 82(1):119–123PubMedCrossRef
go back to reference Sato K, Tomizawa Y, Iijima H, Saito R, Ishizuka T, Nakajima T, Mori M (2006) Epigenetic inactivation of the RUNX3 gene in lung cancer. Oncol Rep 15(1):129–135PubMed Sato K, Tomizawa Y, Iijima H, Saito R, Ishizuka T, Nakajima T, Mori M (2006) Epigenetic inactivation of the RUNX3 gene in lung cancer. Oncol Rep 15(1):129–135PubMed
go back to reference Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61(4):212–236. doi:10.3322/caac.20121 PubMedCrossRef Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61(4):212–236. doi:10.​3322/​caac.​20121 PubMedCrossRef
go back to reference Wheeler CJ, Black KL, Liu G, Mazer M, Zhang XX, Pepkowitz S, Goldfinger D, Ng H, Irvin D, Yu JS (2008) Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res 68(14):5955–5964. doi:10.1158/0008-5472.CAN-07-5973 PubMedCrossRef Wheeler CJ, Black KL, Liu G, Mazer M, Zhang XX, Pepkowitz S, Goldfinger D, Ng H, Irvin D, Yu JS (2008) Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res 68(14):5955–5964. doi:10.​1158/​0008-5472.​CAN-07-5973 PubMedCrossRef
go back to reference Wu YY, Peck K, Chang YL, Pan SH, Cheng YF, Lin JC, Yang RB, Hong TM, Yang PC (2011) SCUBE3 is an endogenous TGF-beta receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer. Oncogene 30(34):3682–3693. doi:10.1038/onc.2011.85 Wu YY, Peck K, Chang YL, Pan SH, Cheng YF, Lin JC, Yang RB, Hong TM, Yang PC (2011) SCUBE3 is an endogenous TGF-beta receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer. Oncogene 30(34):3682–3693. doi:10.​1038/​onc.​2011.​85
go back to reference Xiao WH, Liu WW (2004) Hemizygous deletion and hypermethylation of RUNX3 gene in hepatocellular carcinoma. World J Gastroenterol 10(3):376–380PubMed Xiao WH, Liu WW (2004) Hemizygous deletion and hypermethylation of RUNX3 gene in hepatocellular carcinoma. World J Gastroenterol 10(3):376–380PubMed
Metadata
Title
RUNX3 expression is lost in glioma and its restoration causes drastic suppression of tumor invasion and migration
Authors
Peng-Jin Mei
Jin Bai
Hui Liu
Chen Li
Yong-Ping Wu
Zheng-Quan Yu
Jun-Nian Zheng
Publication date
01-12-2011
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 12/2011
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-011-1063-4

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