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

doi:10.1016/j.isci.2023.106478

Tumor-suppressive role of the musculoaponeurotic fibrosarcoma gene in colorectal cancer

iScience. 2023 Mar 23;26(4):106478. doi: 10.1016/j.isci.2023.106478. eCollection 2023 Apr 21.

Authors

Hiroaki Itakura¹, Tsuyoshi Hata¹, Daisuke Okuzaki^{2

3}, Koki Takeda¹, Kenji Iso⁴, Yamin Qian⁴, Yoshihiro Morimoto¹, Tomohiro Adachi⁵, Haruka Hirose⁴, Yuhki Yokoyama⁴, Takayuki Ogino¹, Norikatsu Miyoshi¹, Hidekazu Takahashi¹, Mamoru Uemura¹, Tsunekazu Mizushima⁶, Takao Hinoi⁷, Masaki Mori⁸, Yuichiro Doki¹, Hidetoshi Eguchi¹, Hirofumi Yamamoto^{1

4}

Affiliations

¹ Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan.
² Genome Information Research Centre, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Suita, Osaka 565-0871, Japan.
³ Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Research Center, Osaka University, Yamadaoka 3-1, Suita, Osaka 565-0871, Japan.
⁴ Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita, Osaka 565-0871, Japan.
⁵ Department of Surgery, Hiroshima City North Medical Center Asa Citizens Hospital, 1-2-1, Kameyama-minami, Asakita-ku, Horoshima 731-0293, Japan.
⁶ Department of Surgery, Osaka Police Hospital, 10-31, Kitayama-town, Tennoji-ku, Osaka city, Osaka 543-0035, Japan.
⁷ Department of Clinical and Molecular Genetics, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
⁸ Department of Surgery, Graduate School of Medical Sciences, Tokai University, 143, Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

Abstract

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.

Keywords: Cancer; Molecular biology; Molecular mechanism of gene regulation.