|Frequent inactivation of axon guidance molecule RGMA in human colon cancer through genetic and epigenetic mechanisms.|
|PMID: 19303019 Owner: NLM Status: MEDLINE|
|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.
|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|
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|Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-03-18|
|Title: Gastroenterology Volume: 137 ISSN: 1528-0012 ISO Abbreviation: Gastroenterology Publication Date: 2009 Jul|
|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|
|Languages: eng Pagination: 176-87 Citation Subset: AIM; IM|
|Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.|
|APA/MLA Format Download EndNote Download BibTex|
Cell Line, Tumor
Cell Movement / genetics
Colonic Neoplasms / genetics*, metabolism, pathology
DNA Mismatch Repair / genetics
Gene Expression Regulation, Neoplastic*
Genes, Tumor Suppressor*
Membrane Proteins / genetics*, metabolism
Nerve Tissue Proteins / genetics*, metabolism
Promoter Regions, Genetic
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins B-raf / genetics
ras Proteins / genetics
|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 126.96.36.199/BRAF protein, human; EC 188.8.131.52/Proto-Oncogene Proteins B-raf; EC 184.108.40.206/ras Proteins|
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