title: DNA hypomethylation at the CpG island is involved in aberrant expression of the L1 cell adhesion molecule gene in colorectal cancer.
abstract: The L1 cell adhesion molecule (L1CAM) has been identified as a target gene of beta-catenin-TCF signaling in colorectal cancer (CRC) and associated with aggressive tumor behavior such as invasion and metastasis. We investigated the methylation status at the L1CAM gene promoter and/or L1CAM mRNA/protein expression in 4 CRC cell lines and 71 primary CRCs. Aberrant L1CAM expression was immuno histochemically observed in 31 (43.7%) of 71 cases, and correlated with advanced stage and presence of lymph node and distant metastases (P<0.05). Treatment with a demethylating agent induced L1CAM mRNA/protein expression in two cell lines lacking L1CAM expression. Bisulfite-modified genome sequencing suggested that DNA methylation status at core promoter and putative TCF-binding sites within the L1CAM promoter was correlated with L1CAM mRNA/protein expression in 4 CRC cell lines. Using the crypt isolation followed by bisulfite-modified genome sequencing and methylation-specific PCR methods, we confirmed that the DNA hypomethylation at core promoter and putative TCF-binding sites was well correlated with the aberrant L1CAM protein expression in primary CRC samples. These results suggest that DNA hypomethylation at the L1CAM CpG islands might induce L1CAM aberrant expression and contribute to the acquisition of aggressive tumor behavior in CRC.
authors.affiliation: Department of Pathology, Iwate Medical University School of Medicine, 18-1 Uchimaru, Morioka, Japan.
authors.forename: Kuniyuki
authors.initials: K
authors.lastname: Kato
authors.forename: Chihaya
authors.initials: C
authors.lastname: Maesawa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Itabashi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Fujisawa
authors.forename: Koki
authors.initials: K
authors.lastname: Otsuka
authors.forename: Shoji
authors.initials: S
authors.lastname: Kanno
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tada
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tatemichi
authors.forename: Koji
authors.initials: K
authors.lastname: Kotani
authors.forename: Hiroki
authors.initials: H
authors.lastname: Oikawa
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sugai
authors.forename: Go
authors.initials: G
authors.lastname: Wakabayashi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Masuda
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D009367:Neoplasm Staging; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D039842:Neural Cell Adhesion Molecule L1; D012333:RNA, Messenger