DNA hypomethylation at the CpG island is involved in aberrant expression of the L1 cell adhesion molecule gene in colorectal cancer.
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.
Kato
Kuniyuki
K
Department of Pathology, Iwate Medical University School of Medicine, 18-1 Uchimaru, Morioka, Japan.
Maesawa
Chihaya
C
Itabashi
Tetsuya
T
Fujisawa
Kentaro
K
Otsuka
Koki
K
Kanno
Shoji
S
Tada
Hiroshi
H
Tatemichi
Yoshinori
Y
Kotani
Koji
K
Oikawa
Hiroki
H
Sugai
Tamotsu
T
Wakabayashi
Go
G
Masuda
Tomoyuki
T
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
D014408:Biomarkers, Tumor; D039842:Neural Cell Adhesion Molecule L1; D012333:RNA, Messenger