Epigenetic silencing of NTSR1 is associated with lateral and noninvasive growth of colorectal tumors
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Seiko Kamimae1,*, Eiichiro Yamamoto1,2,*, Masahiro Kai1,*, Takeshi Niinuma1,2, Hiro-o Yamano3, Masanori Nojima4, Kennjiro Yoshikawa3, Tomoaki Kimura3, Ryo Takagi3, Eiji Harada3, Taku Harada1, Reo Maruyama1,2, Yasushi Sasaki5, Takashi Tokino5, Yasuhisa Shinomura2, Tamotsu Sugai6, Kohzoh Imai7, Hiromu Suzuki1
1Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
2Department of Gastroenterology, Rheumatology, Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan
3Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan
4Center for Translational Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
5Medical Genome Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
6Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
7Center for Medical Innovation, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
*These authors have contributed equally to this work
Hiromu Suzuki, e-mail: email@example.com
Eiichiro Yamamoto, e-mail: firstname.lastname@example.org
Keywords: colorectal tumor, invasion, LST, DNA methylation, biomarker
Received: April 08, 2015 Accepted: August 07, 2015 Published: August 17, 2015
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.
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