MicroRNA-375 suppresses human colorectal cancer metastasis by targeting Frizzled 8

// Lingling Xu 1, * , Tao Wen 2, * , Zhe Liu 1 , Feng Xu 1 , Lei Yang 2 , Jian Liu 2 , Guosheng Feng 1 , Guangyu An 1 1 Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China 2 Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China * These two authors contributed equally to this work Correspondence to: Guangyu An, email: anguangyu@hotmail.com Guosheng Feng, email: fgs010@163.com Keywords: colorectal cancer, microRNA-375, metastasis, FZD8 Received: December 20, 2015     Accepted: May 17, 2016     Published: June 3, 2016 ABSTRACT microRNAs are aberrantly expressed during the development and progression of a variety of human cancers, including colorectal cancer (CRC). Of these microRNAs, microRNA-375 (miR-375) was previously observed to be downregulated in human colorectal cancer(CRC) plasma and tissues, but its functions are largely unknown. Here, we investigated the impact of miR-375 on CRC metastasis. Specifically, miR-375 expression was significantly decreased in human CRC tissues compared with their matched noncancerous tissues (NCTs), and low levels of miR-375 predicted tumor metastatic potential. The up-regulation of miR-375 suppressed colorectal cancer cell migration and invasion in vitro and reduced tumor metastases in murine models established by both orthotopic implantation and spleen injection. Furthermore, we identified Frizzled 8 (FZD8) as a direct target of miR-375 in CRC, and miR-375 negatively regulated Wnt/β-catenin signaling by suppressing FZD8. More importantly, FZD8 expression inversely correlated with overall survival in human CRC patients and is a likely independent predictor of survival. Therefore, we concluded that miR-375 functions as a tumor-suppressive microRNA by directly acting upon FZD8, which may serve as a new therapeutic target to inhibit tumor metastasis in CRC.