Tumor-suppressive role of the musculoaponeurotic fibrosarcoma gene in colorectal cancer
Hiroaki Itakura,
Tsuyoshi Hata,
Daisuke Okuzaki,
Koki Takeda,
Kenji Iso,
Yamin Qian,
Yoshihiro Morimoto,
Tomohiro Adachi,
Haruka Hirose,
Yuhki Yokoyama,
Takayuki Ogino,
Norikatsu Miyoshi,
Hidekazu Takahashi,
Mamoru Uemura,
Tsunekazu Mizushima,
Takao Hinoi,
Masaki Mori,
Yuichiro Doki,
Hidetoshi Eguchi,
Hirofumi Yamamoto
Affiliations
Hiroaki Itakura
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
Tsuyoshi Hata
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
Daisuke Okuzaki
Genome Information Research Centre, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Suita, Osaka 565-0871, Japan; Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Research Center, Osaka University, Yamadaoka 3-1, Suita, Osaka 565-0871, Japan
Koki Takeda
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
Kenji Iso
Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan
Yamin Qian
Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan
Yoshihiro Morimoto
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
Tomohiro Adachi
Department of Surgery, Hiroshima City North Medical Center Asa Citizens Hospital, 1-2-1, Kameyama-minami, Asakita-ku, Horoshima 731-0293, Japan
Haruka Hirose
Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan
Yuhki Yokoyama
Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan
Takayuki Ogino
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
Norikatsu Miyoshi
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
Hidekazu Takahashi
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
Mamoru Uemura
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
Tsunekazu Mizushima
Department of Surgery, Osaka Police Hospital, 10-31, Kitayama-town, Tennoji-ku, Osaka city, Osaka 543-0035, Japan
Takao Hinoi
Department of Clinical and Molecular Genetics, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan
Masaki Mori
Department of Surgery, Graduate School of Medical Sciences, Tokai University, 143, Shimokasuya, Isehara, Kanagawa 259-1193, Japan
Yuichiro Doki
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
Hidetoshi Eguchi
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan
Hirofumi Yamamoto
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan; Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan; Corresponding author
Summary: Somatic cell reprogramming using the microRNAs miR-200c, miR-302s, and miR-369s leads to increased expression of cyclin-dependent kinase inhibitors in human colorectal cancer (CRC) cells and suppressed tumor growth. Here, we investigated whether these microRNAs inhibit colorectal tumorigenesis in CPC;Apc mice, which are prone to colon and rectal polyps. Repeated administration of microRNAs inhibited polyp formation. Microarray analysis indicated that c-MAF, which reportedly shows oncogene-like behavior in multiple myeloma and T cell lymphoma, decreased in tumor samples but increased in microRNA-treated normal mucosa. Immunohistochemistry identified downregulation of c-MAF as an early tumorigenesis event in CRC, with low c-MAF expression associated with poor prognosis. Of note, c-MAF expression and p53 protein levels were inversely correlated in CRC samples. c-MAF knockout led to enhanced tumor formation in azoxymethane/dextran sodium sulfate–treated mice, with activation of cancer-promoting genes. c-MAF may play a tumor-suppressive role in CRC development.
