Epigenetic silencing of NTSR1 is associated with lateral and noninvasive growth of colorectal tumors.
Our aim was to identify DNA methylation changes associated with the growth pattern and invasiveness of colorectal cancers (CRCs). Comparison of the methylation statuses of large (≥ 20 mm in diameter along the colonic surface) noninvasive tumors (NTs) and small (<20 mm in diameter along the colonic surface) invasive tumors (ITs) using CpG island microarray analysis showed neurotensin receptor 1 (NTSR1) to be hypermethylated in large NTs. Quantitative bisulfite pyrosequencing revealed that NTSR1 is frequently methylated in colorectal tumors, with large NTs exhibiting the highest methylation levels. The higher NTSR1 methylation levels were associated with better prognoses. By contrast, NTSR1 copy number gains were most frequent among small ITs. Methylation of NTSR1 was associated with the gene's silencing in CRC cell lines, whereas ectopic expression of NTSR1 promoted proliferation and invasion by CRC cells. Analysis of primary tumors composed of adenomatous and malignant portions revealed that NTSR1 is frequently methylated in the adenomatous portion, while methylation levels are generally lower in the cancerous portions. These results suggest that NTSR1 methylation is associated with lateral and noninvasive growth of colorectal tumors, while low levels of methylation may contribute to the malignant potential through activation of NTSR1. Our data also indicate that NTSR1 methylation may be a prognostic biomarker in CRC.
Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Seiko
S
Kamimae
Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Gastroenterology, Rheumatology, Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Eiichiro
E
Yamamoto
Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Masahiro
M
Kai
Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Gastroenterology, Rheumatology, Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Takeshi
T
Niinuma
Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan.
Hiro-o
HO
Yamano
Center for Translational Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Masanori
M
Nojima
Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan.
Kennjiro
K
Yoshikawa
Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan.
Tomoaki
T
Kimura
Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan.
Ryo
R
Takagi
Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan.
Eiji
E
Harada
Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Taku
T
Harada
Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Gastroenterology, Rheumatology, Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Reo
R
Maruyama
Medical Genome Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Yasushi
Y
Sasaki
Medical Genome Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Takashi
T
Tokino
Department of Gastroenterology, Rheumatology, Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Yasuhisa
Y
Shinomura
Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan.
Tamotsu
T
Sugai
Center for Medical Innovation, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Kohzoh
K
Imai
Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Hiromu
H
Suzuki
D000368:Aged; D015153:Blotting, Western; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D034622:RNA Interference; D018028:Receptors, Neurotensin / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000235:genetics
D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor
DNA methylation; LST; biomarker; colorectal tumor; invasion