Inactivation of axon guidance molecule netrin-1 in human colorectal cancer by an epigenetic mechanism

Hironao Nakayama; Hidetaka Ohnuki; Masako Nakahara; Hisayo Nishida-Fukuda; Tomohisa Sakaue; Shinji Fukuda; Shigeki Higashiyama; Yuki Doi; Masahiro Mitsuyoshi; Takashi Okimoto; Giovanna Tosato; Chiaki Kusumoto

doi:10.1016/j.bbrc.2022.04.069

Inactivation of axon guidance molecule netrin-1 in human colorectal cancer by an epigenetic mechanism

Biochem Biophys Res Commun. 2022 Jun 30:611:146-150. doi: 10.1016/j.bbrc.2022.04.069. Epub 2022 Apr 20.

Authors

Affiliations

¹ Department of Medical Science and Technology, Hiroshima International University, Higashi-hiroshima, Hiroshima, 739-2695, Japan. Electronic address: hironao@hirokoku-u.ac.jp.
² Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
³ Department of Medical Science and Technology, Hiroshima International University, Higashi-hiroshima, Hiroshima, 739-2695, Japan.
⁴ Department of Genome Editing, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka, 5731010, Japan.
⁵ Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Shitsukawa, Ehime, 791-0295, Japan; Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Toon, Shitsukawa, Ehime, 791-0295, Japan.
⁶ Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Shitsukawa, Ehime, 791-0295, Japan; Department of Biochemistry, School of Dentistry, Aichi Gakuin University, Nagoya, Aichi, 464-8650, Japan.
⁷ Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Shitsukawa, Ehime, 791-0295, Japan; Department of Molecular and Cellular Biology, Osaka International Cancer Institute, Chuo-ku, Osaka, 541-8567, Japan.
⁸ Department of Surgery, Nippon Kokan Fukuyama Hospital, Fukuyama, Hiroshima, 721-0927, Japan.
⁹ Department of Surgery, Nippon Kokan Fukuyama Hospital, Fukuyama, Hiroshima, 721-0927, Japan; Department of Surgery I, School of Medicine, University of Occupational and Environmental Health, Kita-kyushu, Fukuoka, 807-0804, Japan.
¹⁰ Department of Surgery, Nippon Kokan Fukuyama Hospital, Fukuyama, Hiroshima, 721-0927, Japan; Department of Surgery, Kyushu Rosai Hospital, Kita-kyushu, Fukuoka, 800-0296, Japan.
¹¹ Department of Medical Science and Technology, Hiroshima International University, Higashi-hiroshima, Hiroshima, 739-2695, Japan; Department of Gastroenterology, Nippon Kokan Fukuyama Hospital, Fukuyama, Hiroshima, 721-0927, Japan. Electronic address: kusumoto@hirokoku-u.ac.jp.

Abstract

Netrin-1, the protein product of the NTN1 gene, is an axon guidance molecule implicated in regulation of cell survival and tumorigenesis. Expression of the netrin-1 receptors deleted in colorectal cancer (DCC) and uncoordinated 5 homolog (UNC5H) is frequently silenced in colorectal cancer (CRC) by either loss of heterozygosity or epigenetic mechanisms. However, netrin-1 expression and regulation in CRC are mostly unknown. Here, we report that NTN1 expression is significantly reduced in most CRC tissues compared to the adjacent normal intestinal mucosa, and that NTN1 DNA methylation is significantly higher in CRCs (24.6%) than in the adjacent normal intestinal mucosa (4.0%). In 6 CRC cell lines, NTN1 expression is low. Treatment with 5-Aza-2'-deoxycytidine increased expression of NTN1 in CRC cell lines, indicating that DNA methylation represses NTN1 transcription in CRCs. NTN1 DNA hypermethylation was significantly associated with advanced CRC disease. Median netrin-1 serum levels were significantly decreased in CRC patients (330.1 pg/mL) compared with normal individuals (438.6 pg/mL). Our results suggest that netrin-1 is a candidate biomarker for CRC.

Keywords: Axon guidance; Colorectal cancer; DNA methylation; Netrin-1; VEGF-A.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Axon Guidance
Colorectal Neoplasms* / genetics
Epigenesis, Genetic*
Humans
Netrin Receptors / genetics
Netrin-1* / genetics

Substances

NTN1 protein, human
Netrin Receptors
Netrin-1

Grants and funding

ZIA SC010355/ImNIH/Intramural NIH HHS/United States