Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene 2006 Aug 17;25(36):4986-97
Date
03/29/2006Pubmed ID
16568088Pubmed Central ID
PMC4610155DOI
10.1038/sj.onc.1209505Scopus ID
2-s2.0-33747371948 (requires institutional sign-in at Scopus site) 129 CitationsAbstract
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.
Author List
Wendt MK, Johanesen PA, Kang-Decker N, Binion DG, Shah V, Dwinell MBAuthor
Michael B. Dwinell PhD Director, Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBase Sequence
Chemokine CXCL12
Chemokines, CXC
Colorectal Neoplasms
CpG Islands
DNA Methylation
DNA Modification Methylases
DNA Primers
Gene Silencing
Humans
Immunohistochemistry
Mice
Mice, SCID
Microscopy, Fluorescence
Neoplasm Metastasis
Promoter Regions, Genetic
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction