Companion Diagnostic and Cancer Biomarkers Decreased miR-340 Expression in Bone Marrow Is Associated with Liver Metastasis of Colorectal Cancer

Studies have shown the prognostic significance of disseminated tumor cells (DTC) in bone marrow of patients with colorectal cancer. However, the molecular characteristics of DTCs, including their miRNA expression profiles, remain mostly unknown. In this study, we analyzed the miRNA expression of DTCs in bone marrow. EpCAMþ bone marrow cells were collected using immunomagnetic beads after exclusion of CD14þ and CD45þ cells, then subjected to miRNA microarray analysis. Cluster analysis (7 colorectal cancer patientswith livermetastasis and 12 colorectal cancer patientswithout livermetastasis) indicated thatmiR-340 andmiR-542-3p expressions were significantly decreased in EpCAMþ bonemarrow cells of patients with liver metastasis (P 1⁄4 0.019 and 0.037, respectively). We demonstrated that pre-miR-340 administration inhibited growth of colon cancer cells and suppressed c-Met expression in vitro. In clinical samples of colorectal cancer, miR-340 was expressed at significantly lower levels in tumor tissues compared with normal mucosa. Survival analysis in 136 patients with colorectal cancer indicated that low miR-340 expression was correlated with shorter 5-year disease-free survival (P1⁄4 0.023) and poor 5-year overall survival (P1⁄4 0.046). It was of note that the colorectal cancer group with low miR-340 and high c-Met expression had the worst prognosis. We further demonstrated that systemic pre-miR-340 administration suppressed growth of pre-established HCT116 tumors in animal therapeuticmodels. These findings indicate thatmiR-340may be useful as a novel prognostic factor and as a therapeutic tool against colorectal cancer. Our data suggest that miR-340 in bone marrow may play an important role in regulating the metastasis cascade of colorectal cancer.Mol Cancer Ther; 13(4); 976–85.