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. EpCAM(+) bone marrow cells were collected using immunomagnetic beads after exclusion of CD14(+) and CD45(+) cells, then subjected to miRNA microarray analysis. Cluster analysis (7 colorectal cancer patients with liver metastasis and 12 colorectal cancer patients without liver metastasis) indicated that miR-340 and miR-542-3p expressions were significantly decreased in EpCAM(+) bone marrow cells of patients with liver metastasis (P = 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 (P = 0.023) and poor 5-year overall survival (P = 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 therapeutic models. These findings indicate that miR-340 may 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.
Authors' Affiliations: Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University; Department of Surgery, Nishinomiya Municipal Central Hospital; Department of Surgery, Minoh City Hospital; Department of Surgery, Suita Municipal Hospital; Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases; Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka;Department of Surgery, Kansai Rosai Hospital, Hyogo; and Department of Surgery, Kyushu University Beppu Hospital, Oita, Japan.
Hiroshi
H
Takeyama
Hirofumi
H
Yamamoto
Shinya
S
Yamashita
Xin
X
Wu
Hidekazu
H
Takahashi
Junichi
J
Nishimura
Naotsugu
N
Haraguchi
Yasuhiro
Y
Miyake
Rei
R
Suzuki
Kohei
K
Murata
Masayuki
M
Ohue
Takeshi
T
Kato
Ichiro
I
Takemasa
Tsunekazu
T
Mizushima
Hideshi
H
Ishii
Koshi
K
Mimori
Yuichiro
Y
Doki
Masaki
M
Mori
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism*; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics
C570046:MIRN340 microRNA, human; C572357:MIRN542 microRNA, human; D035683:MicroRNAs; D019859:Proto-Oncogene Proteins c-met