574506

MIR503

microRNA 503;MIR503;microRNA 503

-

Xq26.3

ncRNA

TGFbeta signaling is known to drive metastasis in human cancer. Under physiologic conditions, the level of TGFbeta activity is tightly controlled by a regulatory network involving multiple negative regulators. At metastasis, however, these inhibitory mechanisms are usually overridden so that oncogenic TGFbeta signaling can be overactivated and sustained. To better understand how the TGFbeta inhibitors are suppressed in metastatic breast cancer cells, we compared miRNA expression profiles between breast cancers with or without metastasis and found that the miR424-503 cluster was markedly overexpressed in metastatic breast cancer. Mechanistic studies revealed that miR424 and miR503 simultaneously suppressed Smad7 and Smurf2, two key inhibitory factors of TGFbeta signaling, leading to enhanced TGFbeta signaling and metastatic capability of breast cancer cells. Moreover, antagonizing miR424-503 in breast cancer cells suppressed metastasis in vivo and increased overall host survival. Interestingly, our study also found that heterogeneous expression of the miR424-503 cluster contributed to the heterogeneity of TGFbeta activity levels in, and metastatic potential of, breast cancer cell subsets. Overall, our findings demonstrate a novel mechanism, mediated by elevated expression of the miR424-503 cluster, underlying TGFbeta activation and metastasis of human breast cancer.

BACKGROUND AND OBJECTIVES: metastasis of cancer is a complex process that involves multiple alterations. Recent evidence indicates that small non-protein coding RNA molecules (miRNAs) might be involved in cancer-related processes in humans. This study was to systematically investigate the differentially expressed miRNAs during metastasis in hepatocellular carcinoma (HCC) using microarray technology. METHODS: The differentially expressed miRNAs between HCCLM3 and MHCC97-L, two HCC cell lines with differently metastatic potentials were displayed using microarray technology. The expression of miR-503 was verified by the real-time quantitative polymerase chain reaction. In addition, the lentivirus-delivered system for expressing miR-503 in HCCLM3 cells was employed to investigate whether miR-503 was involved in invasive phenotype of HCC cell. RESULTS: Our study built a metastasis-related miRNAs expression profiling, which includes 327 miRNAs expressed differentially between HCCLM3 and MHCC97-L cell lines. Furthermore, expression of miR-503 by lentivirus-delivered system in HCCLM3 cell was established successfully. Our results showed that miR-503 induces a G1 arrest and decreased proliferation for HCCLM3 cell (P < 0.05). In addition, miR-503 inhibits migration and invasion of HCCLM3 cell in vitro (P < 0.05). CONCLUSIONS: This study described a metastasis-related miRNAs expression profiling and revealed miR-503 regulating metastatic function in HCC cell.

BACKGROUND: Our previous work described a metastasis-related microRNAs expression profiling and revealed miR-503 regulating metastatic function in hepatocellular carcinoma (HCC) cells. Here, we investigate to define the mechanism of miR-503 regulating metastasis in HCC. MATERIALS AND METHODS: The expressions of miR-503 in HCC cell lines and clinical tissues with different metastatic potential were investigated. Meanwhile, a metastatic human HCC cell BALB/c nude mice model was used to investigate whether miR-503 regulates metastasis of HCC in vivo. Furthermore, luciferase activity of reporter gene, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), fluorescence-activated cell sorting analysis (FACS), and invasion assay were carried out to characterize the mechanism of miR-503 regulating metastasis in HCC. RESULTS: We confirmed the negative correlation between miR-503 expression and metastatic potential of HCC in cell lines and in clinical HCC tissues. We also showed that overexpression of miR-503 resulted in inhibition of proliferation and metastasis of HCC in vivo. Furthermore, we demonstrated that ARHGEF19 is a direct target gene of miR-503. Finally, our results indicated that ARHGEF19 overcomes the suppressive influence of miR-503 in HCC cells. CONCLUSIONS: Our results suggest an important role of miR-503 in inhibiting metastasis of HCC through deregulating ARHGEF19.