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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2016; 22(2): 557-566
Published online Jan 14, 2016. doi: 10.3748/wjg.v22.i2.557
Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer
Katsuhiko Nosho, Yasutaka Sukawa, Yasushi Adachi, Miki Ito, Kei Mitsuhashi, Hiroyoshi Kurihara, Shinichi Kanno, Itaru Yamamoto, Keisuke Ishigami, Hisayoshi Igarashi, Reo Maruyama, Kohzoh Imai, Hiroyuki Yamamoto, Yasuhisa Shinomura
Katsuhiko Nosho, Yasutaka Sukawa, Yasushi Adachi, Miki Ito, Kei Mitsuhashi, Hiroyoshi Kurihara, Shinichi Kanno, Itaru Yamamoto, Keisuke Ishigami, Hisayoshi Igarashi, Yasuhisa Shinomura, Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan
Reo Maruyama, Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan
Kohzoh Imai, Division of Cancer Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Hiroyuki Yamamoto, Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
Author contributions: Nosho K designed the report, analyzed the data and wrote the manuscript; Adachi Y and Maruyama R analyzed the data; Ito M, Mitsuhashi K, Kurihara H, Kanno S, Yamamoto I, Ishigami K and Igarashi H performed experiments; Sukawa Y, Adachi Y, Imai K, Yamamoto H and Shinomura Y edited the manuscript.
Supported by Japanese Society of Gastroenterology Research Foundation (to Nosho K); Pancreas Research Foundation of Japan (to Nosho K); Medical Research Encouragement Prize of The Japan Medical Association (to Nosho K); The Japan Society for the Promotion of Science Challenging Exploratory Research, grant No. 25670371 (to Shinomura Y); and Ono Cancer Research Foundation (to Ito M).
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Katsuhiko Nosho, MD, PhD, Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. nosho@sapmed.ac.jp
Telephone: +81-11-6112111 Fax: +81-11-6112282
Received: June 30, 2015
Peer-review started: July 4, 2015
First decision: September 11, 2015
Revised: September 25, 2015
Accepted: November 13, 2015
Article in press: November 13, 2015
Published online: January 14, 2016
Processing time: 190 Days and 7.6 Hours
Abstract

The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6% (44/511), which was lower than that in United States cohort studies (13%). Similar to the United States studies, F. nucleatum positivity in Japanese colorectal cancers was significantly associated with microsatellite instability (MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets (i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain microRNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. MicroRNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may provide insights for strategies to target microbiota, immune cells and tumor molecular alterations for colorectal cancer prevention and treatment. Further investigation is needed to clarify the association of Fusobacterium with T-cells and microRNA expressions in colorectal cancer.

Keywords: BRAF; CpG island methylator phenotype; Colon neoplasia; Fusobacterium species; miR-21

Core tip: The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue. Our results showed that the frequency of F. nucleatum positivity in Japanese colorectal cancer was 8.6%, which was lower than that in United States cohort studies (13%). F. nucleatum positivity was significantly associated with microsatellite instability-high status. Additionally, F. nucleatum possesses immunosuppressive activities by inhibiting T-cell responses. Thus, emerging evidence may provide insights for strategies to target microbiota, immune cells, and molecular alterations for colorectal cancer prevention and treatment.