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Journal of Cancer Research and Clinical Oncology

Published in:

01-01-2009 | Original Paper

Down-regulation of CXCL12 mRNA expression by promoter hypermethylation and its association with metastatic progression in human breast carcinomas

Authors: Wei Zhou, Zheng Jiang, Ningbo Liu, Fenghua Xu, Peie Wen, Yanbing Liu, Weixia Zhong, Xianrang Song, Xiaotian Chang, Xiuli Zhang, Guangsheng Wei, Jinming Yu

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2009

Abstract

Purpose

Not only is the expression of CXCR4 on breast cancers a key determinant of tumor metastasis, CXCL12 exhibiting peak levels of constitutive expression in organs representing the first destinations of cancer metastasis, but is proposed to be also essential for the organ-specific metastatic process.

Methods

In this study, the expressions of CXCR4 and CXCL12 were investigated using quantitative RT-PCR and immunohistochemistry in samples of 63 primary breast carcinomas and 20 normal breast tissues. Using methylation-specific PCR, we also analyzed the methylation status of CXCL12.

Results

Both up-regulation of CXCR4 and down-regulation of CXCL12 were observed in primary breast carcinomas. Over-expression of CXCR4 mRNA was significantly related to lymph node metastasis status and strong Her-2 expression, while decreased expression of CXCL12 mRNA was significantly associated with positive lymph node metastasis and estrogen receptor negativity. Methylation-specific PCR showed that 52.4% of breast tumors were hypermethylated in the CXCL12 promoter region. The expression levels of DNA methyltransferase (DNMT) 1 and DNMT3B were significantly higher in the CXCL12-methylated breast carcinomas than in the CXCL12-unmethylated ones.

Conclusions

In summary, DNA hypermethylation of CXCL12 plays an important role in the down-regulation of CXCL12 expression in breast carcinomas. Cancer cells lacking expression of CXCL12, but maintaining over-expression of CXCR4, can selectively spread to target organs in which the ligand is highly secreted.

Andre F, Cabioglu N, Assi H, Sabourin JC, Delaloge S, Sahin A et al (2006) Expression of chemokine receptors predicts the site of metastatic relapse in patients with axillary node positive primary breast cancer. Ann Oncol 17:945–951. doi:10.1093/annonc/mdl053 PubMedCrossRef

Arya M, Ahmed H, Silhi N, Williamson M, Patel HR (2007) Clinical importance and therapeutic implications of the pivotal CXCL12-CXCR4 (chemokine ligand-receptor) interaction in cancer cell migration. Tumour Biol 28:123–131. doi:10.1159/000102979 PubMedCrossRef

Barbero S, Bonavia R, Bajetto A, Porcile C, Pirani P, Ravetti JL et al (2003) Stromal cell-derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt. Cancer Res 63:1969–1974PubMed

Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9:2395–2402. doi:10.1093/hmg/9.16.2395 PubMedCrossRef

Caldeira JR, Prando EC, Quevedo FC, Neto FA, Rainho CA, Rogatto SR (2006) CDH1 promoter hypermethylation and E-cadherin protein expression in infiltrating breast cancer. BMC Cancer 6:48. doi:10.1186/1471-2407-6-48 PubMedCrossRef

Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572. doi:10.1038/nrc865 PubMedCrossRef

Davis DA, Singer KE, De La Luz Sierra M, Narazaki M, Yang F, Fales HM et al (2005) Identification of carboxypeptidase N as an enzyme responsible for C-terminal cleavage of stromal cell-derived factor-1alpha in the circulation. Blood 105:4561–4568. doi:10.1182/blood-2004-12-4618 PubMedCrossRef

Girault I, Tozlu S, Lidereau R, Bièche I (2003) Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas. Clin Cancer Res 9:4415–4422PubMed

Grunau C, Clark SJ, Rosenthal A (2001) Bisulfite genomic sequencing: systematic investigation of critical experimental parameters. Nucleic Acids Res 29:E65. doi:10.1093/nar/29.13.e65 PubMedCrossRef

Jiang Z, Li X, Hu J, Zhou W, Jiang Y, Li G et al (2006) Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci Res 56:450–458. doi:10.1016/j.neures.2006.09.006 PubMedCrossRef

Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordón-Cardo C et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3:537–549. doi:10.1016/S1535-6108(03)00132-6 PubMedCrossRef

Kang H, Watkins G, Parr C, Douglas-Jones A, Mansel RE, Jiang WG (2005) Stromal cell derived factor-1: its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer. Breast Cancer Res 7:R402–R410. doi:10.1186/bcr1022 PubMedCrossRef

Kato M, Kitayama J, Kazama S, Nagawa HBB (2003) Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma. Breast Cancer Res 5:R144–R150. doi:10.1186/bcr627 PubMedCrossRef

Kim J, Mori T, Chen SL, Amersi FF, Martinez SR, Kuo C et al (2006) Chemokine receptor CXCR4 expression in patients with melanoma and colorectal cancer liver metastases and the association with disease outcome. Ann Surg 244:113–120. doi:10.1097/01.sla.0000217690.65909.9c PubMedCrossRef

Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsuji S, Nakajima S et al (2000) Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res 6:3530–3535PubMed

Kwon YM, Park JH, Kim H, Shim YM, Kim J, Han J et al (2007) Different susceptibility of increased DNMT1 expression by exposure to tobacco smoke according to histology in primary non-small cell lung cancer. J Cancer Res Clin Oncol 133:219–226. doi:10.1007/s00432-006-0160-2 PubMedCrossRef

Lapidus RG, Nass SJ, Davidson NE (1998) The loss of estrogen and progesterone receptor gene expression in human breast cancer. J Mammary Gland Biol Neoplasia 3:85–94. doi:10.1023/A:1018778403001 PubMedCrossRef

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408. doi:10.1006/meth.2001.1262 PubMedCrossRef

Luker KE, Luker GD (2006) Functions of CXCL12 and CXCR4 in breast cancer. Cancer Lett 238:30–41. doi:10.1016/j.canlet.2005.06.021 PubMedCrossRef

Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al (2001) Involvement of chemokine receptors in breast cancer metastases. Nature 410:50–56. doi:10.1038/35065016 PubMedCrossRef

Robertson KD (2001) DNA methylation, methyltransferases, and cancer. Oncogene 20:3139–3155. doi:10.1038/sj.onc.1204341 PubMedCrossRef

Scotton CJ, Wilson JL, Scott K, Stamp G, Wilbanks GD, Fricker S et al (2002) Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res 62:5930–5938PubMed

Shim H, Lau SK, Devi S, Yoon Y, Cho HT, Liang Z (2006) Lower expression of CXCR4 in lymph node metastases than in primary breast cancers: potential regulation by ligand-dependent degradation and HIF-1alpha. Biochem Biophys Res Commun 346:252–258. doi:10.1016/j.bbrc.2006.05.110 PubMedCrossRef

Siedlecki P, Zielenkiewicz P (2006) Mammalian DNA methyltransferases. Acta Biochim Pol 53:245–256PubMed

Sowińska A, Jagodzinski PP (2007) RNA interference-mediated knockdown of DNMT1 and DNMT3B induces CXCL12 expression in MCF-7 breast cancer and AsPC1 pancreatic carcinoma cell lines. Cancer Lett 255:153–159. doi:10.1016/j.canlet.2007.04.004 PubMedCrossRef

Sutton A, Friand V, Brulé-Donneger S, Chaigneau T, Ziol M, Sainte-Catherine O et al (2007) Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion. Mol Cancer Res 5:21–33. doi:10.1158/1541-7786.MCR-06-0103 PubMedCrossRef

Valenzuela-Fernández A, Planchenault T, Baleux F, Staropoli I, Le-Barillec K, Leduc D et al (2002) Leukocyte elastase negatively regulates stromal cell-derived factor-1 (SDF-1)/CXCR4 binding and functions by amino-terminal processing of SDF-1 and CXCR4. J Biol Chem 277:15677–15689. doi:10.1074/jbc.M111388200 PubMedCrossRef

Waha A, Güntner S, Huang TH, Yan PS, Arslan B, Pietsch T et al (2005) Epigenetic silencing of the protocadherin family member PCDH-gamma-A11 in astrocytomas. Neoplasia 7:193–199. doi:10.1593/neo.04490 PubMedCrossRef

Wendt MK, Johanesen PA, Kang-Decker N, Binion DG, Shah V, Dwinell MB (2006) Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene 25:4986–4997. doi:10.1038/sj.onc.1209505 PubMedCrossRef

Wendt MK, Cooper AN, Dwinell MB (2008) Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells. Oncogene 27:1461–1471. doi:10.1038/sj.onc.1210751 PubMedCrossRef

World Health Organisation (1981) International histological classification of tumours No. 2. Histological typing of breast tumours, 2nd edn. World Health Organisation, Geneva

Yang X, Yan L, Davidson NE (2001) DNA methylation in breast cancer. Endocr Relat Cancer 8:115–127. doi:10.1677/erc.0.0080115 PubMedCrossRef

Zlotnik A (2006) Chemokines and cancer. Int J Cancer 119:2026–2029. doi:10.1002/ijc.22024 PubMedCrossRef

Title: Down-regulation of CXCL12 mRNA expression by promoter hypermethylation and its association with metastatic progression in human breast carcinomas
Authors: Wei Zhou
Zheng Jiang
Ningbo Liu
Fenghua Xu
Peie Wen
Yanbing Liu
Weixia Zhong
Xianrang Song
Xiaotian Chang
Xiuli Zhang
Guangsheng Wei
Jinming Yu
Publication date: 01-01-2009
Publisher: Springer-Verlag
Published in: Journal of Cancer Research and Clinical Oncology / Issue 1/2009
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-008-0435-x

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Abstract

Purpose

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Conclusions

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