Document Detail


Frequent inactivation of axon guidance molecule RGMA in human colon cancer through genetic and epigenetic mechanisms.
MedLine Citation:
PMID:  19303019     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Repulsive guidance molecule member A (RGMA) is a glycosylphosphatidylinositol-anchored glycoprotein and axon guidance molecule that signals through its receptor, neogenin (NEO1), a homologue of the deleted-in-colorectal cancer (DCC) gene. RGMA also functions as a bone morphogenetic protein (BMP) coreceptor. We studied the potential roles of RGMA and NEO1 in colorectal cancer (CRC) pathogenesis.
METHODS: We analyzed expression of RGMA and NEO1, as well as their epigenetic and genetic changes, in a large series of CRC samples, normal colon tissues, adenomas, and cell lines. These studies were accompanied by in vitro functional assay.
RESULTS: RGMA and NEO1 expression were significantly down-regulated in most CRCs, adenomas, and cell lines. RGMA was frequently silenced by promoter methylation in CRCs (86.7%), adenomas (90.9%), and CRC cell lines (92.3%) but not in normal colon tissues; allelic imbalance of RGMA and NEO1 was observed in 40% and 49% of CRCs, respectively. In CRC samples, reduced RGMA levels were significantly associated with mismatch repair deficiency or mutations in KRAS or BRAF. Exposure to 5-aza-2'-deoxycytidine restored RGMA expression in CRC cell lines. Transfection of RGMA into CRC cells suppressed cell proliferation, migration, and invasion and also increased apoptosis in response to DNA-damaging agent.
CONCLUSIONS: The frequent genetic and epigenetic inactivation of RGMA in CRCs and adenomas along with its in vitro function collectively support its role as a tumor suppressor in colon cells. These findings add to the expanding list of axon guidance molecules with disrupted function during colon carcinogenesis and create new opportunities for early detection and drug development.
Authors:
Vivian S W Li; Siu Tsan Yuen; Tsun Leung Chan; Helen H N Yan; Wai Lun Law; Bonnie H Y Yeung; Annie S Y Chan; Wai Yin Tsui; Samuel So; Xin Chen; Suet Yi Leung
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-03-18
Journal Detail:
Title:  Gastroenterology     Volume:  137     ISSN:  1528-0012     ISO Abbreviation:  Gastroenterology     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-30     Completed Date:  2009-07-16     Revised Date:  2012-06-21    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  176-87     Citation Subset:  AIM; IM    
Affiliation:
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
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MeSH Terms
Descriptor/Qualifier:
Adenoma / genetics*,  metabolism,  pathology
Allelic Imbalance
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation
Colonic Neoplasms / genetics*,  metabolism,  pathology
DNA Methylation*
DNA Mismatch Repair / genetics
GPI-Linked Proteins
Gene Expression Regulation, Neoplastic*
Gene Silencing*
Genes, Tumor Suppressor*
Humans
Membrane Proteins / genetics*,  metabolism
Mutation
Neoplasm Invasiveness
Nerve Tissue Proteins / genetics*,  metabolism
Promoter Regions, Genetic
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins B-raf / genetics
Transfection
ras Proteins / genetics
Chemical
Reg. No./Substance:
0/GPI-Linked Proteins; 0/KRAS protein, human; 0/Membrane Proteins; 0/Nerve Tissue Proteins; 0/Proto-Oncogene Proteins; 0/RGMA protein, human; 0/neogenin; EC 2.7.11.1/BRAF protein, human; EC 2.7.11.1/Proto-Oncogene Proteins B-raf; EC 3.6.5.2/ras Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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