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PMID: 16568088 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis.

Oncogene ·Vol. 25 ·No. 36 ·2006-08-17 ·Pages 4986-97

Wendt MK, Johanesen PA, Kang-Decker N, Binion DG, Shah V, Dwinell MB

Abstract

Cellular metastasis is the most detrimental step in carcinoma disease progression, yet the mechanisms that regulate this process are poorly understood. CXCL12 and its receptor CXCR4 are co-expressed in several tissues and cell types throughout the body and play essential roles in development. Disruption of either gene causes embryonic lethality due to similar defects. Post-natally, CXCL12 signaling has a wide range of effects on CXCR4-expressing cells, including the directed migration of leukocytes, lymphocytes and hematopoietic stem cells. Recently, this signaling axis has also been described as an important regulator of directed carcinoma cell metastasis. We show herein that while CXCR4 expression remains consistent, constitutive colonic epithelial expression of CXCL12 is silenced by DNA hypermethylation in primary colorectal carcinomas as well as colorectal carcinoma-derived cell lines. Inhibition of DNA methyltransferase (Dnmt) enzymes with 5-aza-2'-deoxycytidine or genetic ablation of both Dnmt1 and Dnmt3b prevented promoter methylation and restored CXCL12 expression. Re-expression of functional, endogenous CXCL12 in colorectal carcinoma cells dramatically reduced metastatic tumor formation in mice, as well as foci formation in soft agar. Decreased metastasis was correlated with increased caspase activity in cells re-expressing CXCL12. These data constitute the unique observation that silencing CXCL12 within colonic carcinoma cells greatly enhances their metastatic potential.

MeSH Terms
Animals Base Sequence Chemokine CXCL12 Chemokines, CXC/genetics Colorectal Neoplasms/enzymology,genetics,pathology CpG Islands DNA Methylation DNA Modification Methylases/metabolism DNA Primers Gene Silencing Humans Immunohistochemistry Mice Mice, SCID Microscopy, Fluorescence Neoplasm Metastasis/genetics Promoter Regions, Genetic Reverse Transcriptase Polymerase Chain Reaction Signal Transduction
Chemicals
CXCL12 protein, human Chemokine CXCL12 Chemokines, CXC Cxcl12 protein, mouse DNA Primers DNA Modification Methylases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Wendt M K
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226-0509, USA.
Johanesen P A
Kang-Decker N
Binion D G
Shah V
Dwinell M B
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
0950-9232
DOI
10.1038/sj.onc.1209505
Published
2006-08-17
Epub
2006-00-27
Pages
4986-97
Language
English
Region
England
NLM ID
8711562
PMCID
PMC4610155
Subset
IM
Grants
NIDDK NIH HHS · R01 DK062066 · United States
NIDDK NIH HHS · R56 DK062066 · United States
NIDDK NIH HHS · DK002808 · United States
NIDDK NIH HHS · DK062066 · United States
External Links
PubMed source DOI: 10.1038/sj.onc.1209505 PMC Full Text View journal details
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