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Published in: Journal of Experimental & Clinical Cancer Research 1/2011

Open Access 01-12-2011 | Research

Reduced expression of SMAD4 in gliomas correlates with progression and survival of patients

Authors: Shi-ming He, Zhen-wei Zhao, Yuan Wang, Ji-pei Zhao, Liang Wang, Fang Hou, Guo-dong Gao

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2011

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Abstract

Background

To examine the expression of SMAD4 at gene and protein levels in glioma samples with different WHO grades and its association with survival.

Methods

Two hundreds fifty-two glioma specimens and 42 normal control tissues were collected. Immunochemistry assay, quantitative real-time PCR and Western blot analysis were carried out to investigate the expression of SMAD4. Kaplan-Meier method and Cox's proportional hazards model were used in survival analysis.

Results

Immunohistochemistry showed that SMAD4 expression was decreased in glioma. SMAD4 mRNA and protein levels were both lower in glioma compared to control on real-time PCR and Western blot analysis (both P < 0.001). In addition, its expression levels decrease from grade I to grade IV glioma according to the results of real-time PCR, immunohistochemistry analysis and Western blot. Moreover, the survival rate of SMAD4-positive patients was higher than that of SMAD4-negative patients. We further confirmed that the loss of SMAD4 was a significant and independent prognostic indicator in glioma by multivariate analysis.

Conclusions

Our data provides convincing evidence for the first time that the reduced expression of SMAD4 at gene and protein levels is correlated with poor outcome in patients with glioma. SMAD4 may play an inhibitive role during the development of glioma and may be a potential prognosis predictor of glioma.
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Literature
1.
go back to reference Li X, Wang L, Gu JW, Li B, Liu WP, Wang YG, Zhang X, Zhen HN, Fei Z: Up-regulation of EphA2 and down-regulation of EphrinA1 are associated with the aggressive phenotype and poor prognosis of malignant glioma. Tumour Biol. 2010, 31: 477-488. 10.1007/s13277-010-0060-6.CrossRefPubMed Li X, Wang L, Gu JW, Li B, Liu WP, Wang YG, Zhang X, Zhen HN, Fei Z: Up-regulation of EphA2 and down-regulation of EphrinA1 are associated with the aggressive phenotype and poor prognosis of malignant glioma. Tumour Biol. 2010, 31: 477-488. 10.1007/s13277-010-0060-6.CrossRefPubMed
2.
go back to reference Sun B, Chu D, Li W, Chu X, Li Y, Wei D, Li H: Decreased expression of NDRG1 in glioma is related to tumor progression and survival of patients. J Neurooncol. 2009, 94: 213-219. 10.1007/s11060-009-9859-7.CrossRefPubMed Sun B, Chu D, Li W, Chu X, Li Y, Wei D, Li H: Decreased expression of NDRG1 in glioma is related to tumor progression and survival of patients. J Neurooncol. 2009, 94: 213-219. 10.1007/s11060-009-9859-7.CrossRefPubMed
3.
go back to reference Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J, Perry SR, Labrot ES, Wu X, Lis R, Hoshida Y, Hiller D, Hu B, Jiang S, Zheng H, Stegh AH, Scott KL, Signoretti S, Bardeesy N, Wang YA, Hill DE, Golub TR, Stampfer MJ, Wong WH, Loda M, Mucci L, Chin L, DePinho RA: SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature. 2011, 470: 269-273. 10.1038/nature09677.PubMedCentralCrossRefPubMed Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J, Perry SR, Labrot ES, Wu X, Lis R, Hoshida Y, Hiller D, Hu B, Jiang S, Zheng H, Stegh AH, Scott KL, Signoretti S, Bardeesy N, Wang YA, Hill DE, Golub TR, Stampfer MJ, Wong WH, Loda M, Mucci L, Chin L, DePinho RA: SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature. 2011, 470: 269-273. 10.1038/nature09677.PubMedCentralCrossRefPubMed
4.
go back to reference Ali NA, McKay MJ, Molloy MP: Proteomics of Smad4 regulated transforming growth factor-beta signalling in colon cancer cells. Mol Biosyst. 2010, 6: 2332-2338. 10.1039/c0mb00016g.CrossRefPubMed Ali NA, McKay MJ, Molloy MP: Proteomics of Smad4 regulated transforming growth factor-beta signalling in colon cancer cells. Mol Biosyst. 2010, 6: 2332-2338. 10.1039/c0mb00016g.CrossRefPubMed
5.
go back to reference Papageorgis P, Cheng K, Ozturk S, Gong Y, Lambert AW, Abdolmaleky HM, Zhou JR, Thiagalingam S: Smad4 inactivation promotes malignancy and drug resistance of colon cancer. Cancer Res. 2011, 71: 998-1008. 10.1158/0008-5472.CAN-09-3269.PubMedCentralCrossRefPubMed Papageorgis P, Cheng K, Ozturk S, Gong Y, Lambert AW, Abdolmaleky HM, Zhou JR, Thiagalingam S: Smad4 inactivation promotes malignancy and drug resistance of colon cancer. Cancer Res. 2011, 71: 998-1008. 10.1158/0008-5472.CAN-09-3269.PubMedCentralCrossRefPubMed
6.
go back to reference Sakellariou S, Liakakos T, Ghiconti I, Hadjikokolis S, Nakopoulou L, Pavlakis K: Immunohistochemical expression of P15 (INK4B) and SMAD4 in advanced gastric cancer. Anticancer Res. 2008, 28: 1079-1083.PubMed Sakellariou S, Liakakos T, Ghiconti I, Hadjikokolis S, Nakopoulou L, Pavlakis K: Immunohistochemical expression of P15 (INK4B) and SMAD4 in advanced gastric cancer. Anticancer Res. 2008, 28: 1079-1083.PubMed
7.
go back to reference Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Eshleman JR, Goggins M, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Cameron JL, Olino K, Schulick R, Winter J, Herman JM, Laheru D, Klein AP, Vogelstein B, Kinzler KW, Velculescu VE, Hruban RH: SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009, 15: 4674-4679. 10.1158/1078-0432.CCR-09-0227.PubMedCentralCrossRefPubMed Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Eshleman JR, Goggins M, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Cameron JL, Olino K, Schulick R, Winter J, Herman JM, Laheru D, Klein AP, Vogelstein B, Kinzler KW, Velculescu VE, Hruban RH: SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009, 15: 4674-4679. 10.1158/1078-0432.CCR-09-0227.PubMedCentralCrossRefPubMed
8.
go back to reference Ke Z, Zhang X, Ma L, Wang L: Deleted in pancreatic carcinoma locus 4/Smad4 participates in the regulation of apoptosis by affecting the Bcl-2/Bax balance in non-small cell lung cancer. Hum Pathol. 2008, 39: 1438-1445. 10.1016/j.humpath.2008.03.006.CrossRefPubMed Ke Z, Zhang X, Ma L, Wang L: Deleted in pancreatic carcinoma locus 4/Smad4 participates in the regulation of apoptosis by affecting the Bcl-2/Bax balance in non-small cell lung cancer. Hum Pathol. 2008, 39: 1438-1445. 10.1016/j.humpath.2008.03.006.CrossRefPubMed
9.
go back to reference Lv J, Cao XF, Ji L, Zhu B, Wang DD, Tao L, Li SQ: Association of β-catenin, Wnt1, Smad4, Hoxa9, and Bmi-1 with the prognosis of esophageal squamous cell carcinoma. Med Oncol. 2011, Lv J, Cao XF, Ji L, Zhu B, Wang DD, Tao L, Li SQ: Association of β-catenin, Wnt1, Smad4, Hoxa9, and Bmi-1 with the prognosis of esophageal squamous cell carcinoma. Med Oncol. 2011,
10.
go back to reference Sheehan GM, Kallakury BV, Sheehan CE, Fisher HA, Kaufman RP, Ross JS: Smad4 protein expression correlates with grade, stage, and DNA ploidy in prostatic adenocarcinomas. Hum Pathol. 2005, 36: 1204-1209. 10.1016/j.humpath.2005.08.015.CrossRefPubMed Sheehan GM, Kallakury BV, Sheehan CE, Fisher HA, Kaufman RP, Ross JS: Smad4 protein expression correlates with grade, stage, and DNA ploidy in prostatic adenocarcinomas. Hum Pathol. 2005, 36: 1204-1209. 10.1016/j.humpath.2005.08.015.CrossRefPubMed
11.
go back to reference Hiwatashi K, Ueno S, Sakoda M, Kubo F, Tateno T, Kurahara H, Mataki Y, Maemura K, Ishigami S, Shinchi H, Natsugoe S: Strong Smad4 expression correlates with poor prognosis after surgery in patients with hepatocellular carcinoma. Ann Surg Oncol. 2009, 16: 3176-3182. 10.1245/s10434-009-0614-2.CrossRefPubMed Hiwatashi K, Ueno S, Sakoda M, Kubo F, Tateno T, Kurahara H, Mataki Y, Maemura K, Ishigami S, Shinchi H, Natsugoe S: Strong Smad4 expression correlates with poor prognosis after surgery in patients with hepatocellular carcinoma. Ann Surg Oncol. 2009, 16: 3176-3182. 10.1245/s10434-009-0614-2.CrossRefPubMed
12.
go back to reference Brown RS, Wahl RL: Overexpression of Glut-1 glucose transporter in human breast cancer: an immunohistochemical study. Cancer. 1993, 72: 2979-2985. 10.1002/1097-0142(19931115)72:10<2979::AID-CNCR2820721020>3.0.CO;2-X.CrossRefPubMed Brown RS, Wahl RL: Overexpression of Glut-1 glucose transporter in human breast cancer: an immunohistochemical study. Cancer. 1993, 72: 2979-2985. 10.1002/1097-0142(19931115)72:10<2979::AID-CNCR2820721020>3.0.CO;2-X.CrossRefPubMed
13.
go back to reference Mesker WE, Liefers GJ, Junggeburt JM, van Pelt GW, Alberici P, Kuppen PJ, Miranda NF, van Leeuwen KA, Morreau H, Szuhai K, Tollenaar RA, Tanke HJ: Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients. Cell Oncol. 2009, 31: 169-178.PubMed Mesker WE, Liefers GJ, Junggeburt JM, van Pelt GW, Alberici P, Kuppen PJ, Miranda NF, van Leeuwen KA, Morreau H, Szuhai K, Tollenaar RA, Tanke HJ: Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients. Cell Oncol. 2009, 31: 169-178.PubMed
14.
go back to reference Koinuma D, Tsutsumi S, Kamimura N, Imamura T, Aburatani H, Miyazono K: Promoter-wide analysis of Smad4 binding sites in human epithelial cells. Cancer Sci. 2009, 100: 2133-2142. 10.1111/j.1349-7006.2009.01299.x.CrossRefPubMed Koinuma D, Tsutsumi S, Kamimura N, Imamura T, Aburatani H, Miyazono K: Promoter-wide analysis of Smad4 binding sites in human epithelial cells. Cancer Sci. 2009, 100: 2133-2142. 10.1111/j.1349-7006.2009.01299.x.CrossRefPubMed
15.
go back to reference Bornstein S, White R, Malkoski S, Oka M, Han G, Cleaver T, Reh D, Andersen P, Gross N, Olson S, Deng C, Lu SL, Wang XJ: Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J Clin Invest. 2009, 119: 3408-3419.PubMedCentralPubMed Bornstein S, White R, Malkoski S, Oka M, Han G, Cleaver T, Reh D, Andersen P, Gross N, Olson S, Deng C, Lu SL, Wang XJ: Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J Clin Invest. 2009, 119: 3408-3419.PubMedCentralPubMed
16.
17.
go back to reference Wilentz RE, Su GH, Dai JL, Sparks AB, Argani P, Sohn TA, Yeo CJ, Kern SE, Hruban RH: Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas: a new marker of DPC4 inactivation. Am J Pathol. 2000, 156: 37-43. 10.1016/S0002-9440(10)64703-7.PubMedCentralCrossRefPubMed Wilentz RE, Su GH, Dai JL, Sparks AB, Argani P, Sohn TA, Yeo CJ, Kern SE, Hruban RH: Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas: a new marker of DPC4 inactivation. Am J Pathol. 2000, 156: 37-43. 10.1016/S0002-9440(10)64703-7.PubMedCentralCrossRefPubMed
18.
go back to reference Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH: Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 2000, 60: 2002-2006.PubMed Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH: Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 2000, 60: 2002-2006.PubMed
19.
go back to reference Natsugoe S, Xiangming C, Matsumoto M, Okumura H, Nakashima S, Sakita H, Ishigami S, Baba M, Takao S, Aikou T: Smad4 and Transforming Growth Factor beta1 Expression in Patients with Squamous Cell Carcinoma of the Esophagus. Clin Cancer Res. 2002, 8: 1838-1842.PubMed Natsugoe S, Xiangming C, Matsumoto M, Okumura H, Nakashima S, Sakita H, Ishigami S, Baba M, Takao S, Aikou T: Smad4 and Transforming Growth Factor beta1 Expression in Patients with Squamous Cell Carcinoma of the Esophagus. Clin Cancer Res. 2002, 8: 1838-1842.PubMed
20.
go back to reference Cardillo MR, Lazzereschi D, Gandini O, Di Silverio F, Colletta G: Transforming growth factor-beta pathway in human renal cell carcinoma and surrounding normal-appearing renal parenchyma. Anal Quant Cytol Histol. 2001, 23: 109-117.PubMed Cardillo MR, Lazzereschi D, Gandini O, Di Silverio F, Colletta G: Transforming growth factor-beta pathway in human renal cell carcinoma and surrounding normal-appearing renal parenchyma. Anal Quant Cytol Histol. 2001, 23: 109-117.PubMed
21.
go back to reference Kjellman C, Olofsson SP, Hansson O, Von Schantz T, Lindvall M, Nilsson I, Salford LG, Sjögren HO, Widegren B: Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma. Int J Cancer. 2000, 89: 251-258. 10.1002/1097-0215(20000520)89:3<251::AID-IJC7>3.0.CO;2-5.CrossRefPubMed Kjellman C, Olofsson SP, Hansson O, Von Schantz T, Lindvall M, Nilsson I, Salford LG, Sjögren HO, Widegren B: Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma. Int J Cancer. 2000, 89: 251-258. 10.1002/1097-0215(20000520)89:3<251::AID-IJC7>3.0.CO;2-5.CrossRefPubMed
Metadata
Title
Reduced expression of SMAD4 in gliomas correlates with progression and survival of patients
Authors
Shi-ming He
Zhen-wei Zhao
Yuan Wang
Ji-pei Zhao
Liang Wang
Fang Hou
Guo-dong Gao
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2011
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/1756-9966-30-70

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