Circulating exosomal microRNA-203 is associated with metastasis possibly via inducing tumor-associated macrophages in colorectal cancer

// Yuki Takano 1, 2, * , Takaaki Masuda 1, * , Hisae Iinuma 3 , Rui Yamaguchi 4 , Kuniaki Sato 1 , Taro Tobo 5 , Hidenari Hirata 1 , Yosuke Kuroda 1 , Sho Nambara 1 , Naoki Hayashi 1 , Tomohiro Iguchi 1 , Shuhei Ito 1 , Hidetoshi Eguchi 1 , Takahiro Ochiya 6 , Katsuhiko Yanaga 2 , Satoru Miyano 4 and Koshi Mimori 1 1 Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan 2 Department of Surgery, Jikei University School of Medicine, Tokyo, Japan 3 Department of Surgery, Teikyo University, Tokyo, Japan 4 Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan 5 Department of Pathology, Kyushu University Beppu Hospital, Beppu, Japan 6 Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan * These authors have contributed equally to this work Correspondence to: Koshi Mimori, email: kmimori@beppu.kyushu-u.ac.jp Keywords: miR-203, exosome, tumor-host interaction, tumor-associated macrophage, colorectal cancer Received: March 06, 2017     Accepted: June 26, 2017     Published: August 07, 2017 ABSTRACT A primary tumor can create a premetastatic niche in distant organs to facilitate the development of metastasis. The mechanism by which tumor cells communicate with host cells to develop premetastatic niches is unclear. We focused on the role of microRNA (miR) signaling in promoting metastasis. Here, we identified miR-203 as a signaling molecule between tumors and monocytes in metastatic colorectal cancer (CRC) patients. Notably, high expression of serum exosomal miR-203 , a major form in circulation, was associated with distant metastasis and an independent poor prognostic factor, whereas low expression in tumor tissues was a poor prognostic factor in CRC patients. We also found that exosomes carrying miR-203 from CRC cells were incorporated into monocytes and miR-203 could promote the expression of M2 markers in vitro , suggesting miR-203 promoted the differentiation of monocytes to M2-tumor-associated macrophages (TAMs). In a xenograft mouse model, miR-203 -transfected CRC cells developed more liver metastasis compared to control cells. In conclusion, serum exosomal miR-203 expression is a novel biomarker for predicting metastasis, possibly via promoting the differentiation of monocytes to M2-TAMs in CRC. Furthermore, we propose the concept of site-dependent functions for miR-203 in tumor progression.