442908

MIR340

microRNA 340;MIR340;microRNA 340

-

5q35.3

ncRNA

BACKGROUND: Different microRNAs have been shown to have oncogenic and tumor-suppressive functions in human cancers. Detection of their expression may lead to identifying novel markers for breast cancer. METHODS: The authors detected miR-340 expression in 4 human breast cell lines and then focused on its role in regulation of tumor cell growth, migration, and invasion and target gene expression. They then analyzed miR-340 expression in benign and cancerous breast tissue specimens. RESULTS: Endogenous miR-340 expression was down-regulated in the more aggressive breast cancer cell lines, which was confirmed in breast cancer tissue specimens by using quantitative real-time polymerase chain reaction. Further studies showed that induction of miR-340 expression was able to suppress tumor cell migration and invasion, whereas knockdown of miR-340 expression induced breast cancer cell migration and invasion. At the gene level, the authors identified c-Met as a direct miR-340 target to mediate cell migration and invasion through regulation of MMP-2 and MMP-9 expression. Ex vivo, loss of miR-340 expression was associated with lymph node metastasis, high tumor histological grade, clinical stage, and shorter overall survival of breast cancer as well as increased c-Met expression in breast cancer tissue specimens. CONCLUSIONS: miR-340 may play an important role in breast cancer progression, suggesting that miR-340 should be further evaluated as a novel biomarker for breast cancer metastasis and prognosis, and potentially a therapeutic target.

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.

To investigate the association of combined microRNA-340 (miR-340) and ROCK1 mRNA profiling with clinicopathologic features and prognosis in pediatric patients with osteosarcoma. Quantitative real-time reverse transcriptase-polymerase chain reaction analysis was performed to detect expression levels of miR-340 and ROCK1 mRNA in cancerous and noncancerous bone tissues from 92 children treated for primary osteosarcomas. Compared with noncancerous bone tissues, the expression levels of miR-340 and ROCK1 mRNA were, respectively, downregulated and upregulated in osteosarcoma tissues (both p < 0.001), which was consistent with the results of in situ hybridization and immunohistochemistry analysis. The downregulation of miR-340 was negatively correlated with the upregulation of ROCK1 mRNA in osteosarcoma tissues (r = -0.78, p = 0.001). In addition, the combined miR-340 downregulation and ROCK1 upregulation (miR-340-low/ROCK1-high) occurred more frequently in osteosarcoma tissues with positive metastasis (p < 0.001) and poor response to pre-operative chemotherapy (p = 0.002). Moreover, miR-340-low/ROCK1-high expression was significantly associated with both shortest overall survival (p < 0.001) and progression-free survival (p < 0.001). Multivariate analysis further confirmed that miR-340-low/ROCK1-high expression was an independent prognostic factor of unfavorable survival in pediatric osteosarcoma (for overall survival: p = 0.006, for progression-free survival: p = 0.008). Our data offer convincing evidence, for the first time, that the combined miR-340 downregulation and ROCK1 upregulation may be linked to tumor progression and adverse prognosis in pediatric osteosarcoma.