MiR-122 expression is down-regulated in human HCC. Over-expression of miR-122 inhibits HCC cell growth and promotes the cell apoptosis by affecting Wnt/β-catenin-TCF signalling pathway.

Down-regulation of the microRNA let-7c plays an important role in the pathogenesis of human hepatocellular carcinoma (HCC). The aim of the present study was to determine whether the cell cycle regulator CDC25A is involved in the antitumor effect of let-7c in HCC. The expression levels of let-7c in HCC cell lines were examined by quantitative real-time PCR, and a let-7c agomir was transfected into HCC cells to overexpress let-7c. The effects of let-7c on HCC proliferation, apoptosis and cell cycle were analyzed. The in vivo tumor-inhibitory efficacy of let-7c was evaluated in a xenograft mouse model of HCC. Luciferase reporter assays and western blotting were conducted to identify the targets of let-7c and to determine the effects of let-7c on CDC25A, CyclinD1, CDK6, pRb and E2F2 expression. The results showed that the expression levels of let-7c were significantly decreased in HCC cell lines. Overexpression of let-7c repressed cell growth, induced cell apoptosis, led to G1 cell cycle arrest in vitro, and suppressed tumor growth in a HepG2 xenograft model in vivo. The luciferase reporter assay showed that CDC25A was a direct target of let-7c, and that let-7c inhibited the expression of CDC25A protein by directly targeting its 3ʹ UTR. Restoration of CDC25A induced a let-7c-mediated G1-to-S phase transition. Western blot analysis demonstrated that overexpression of let-7c decreased CyclinD1, CDK6, pRb and E2F2 protein levels. In conclusion, this study indicates that let-7c suppresses HCC progression, possibly by directly targeting the cell cycle regulator CDC25A and indirectly affecting its downstream target molecules. Let-7c may therefore be an effective therapeutic target for HCC.

Hepatocellular carcinoma (HCC) has a high recurrence rate, and patients exhibit poor survival mainly because intrahepatic metastasis is common. We previously reported that let-7c down-regulation is significantly associated with poor differentiation level in HCC. In the present study, we demonstrate that miR-199a-5p and let-7c are frequently down-regulated in HCC cells and tissues, and low expression of miR-199a-5p is correlated with tumor size, liver envelope invasion. Furthermore, miR-199a-5p and let-7c cooperatively inhibit HCC cell migration and invasion in vitro. MAP4K3 is identified as the direct target of miR-199a-5p and let-7c and this regulation is further confirmed by luciferase reporter assays and Western blotting. In addition, MAP4K3 functions as a metastasis promoter since the results demonstrate that MAP4K3 could promote HCC cell migration and invasion. We also find that miR-199a-5p and let-7c increase the sensitivity of HCC cells to sorafenib.ConclusionsWe report that miR-199a-5p and let-7c cooperatively and efficiently inhibit HCC cell migration and invasion by targeting the metastasis promoter MAP4K3 and MAP4K3-mediated drug sensitization, suggesting that the use of miRNAs and sorafenib in combination therapy may be a powerful approach to the treatment of HCC.

Although extensive investigation has been made on miR-29a in relation to malignancies, only a little information has been provided about the angiogenic property of this miRNA so far. Herein, we sought to investigate the role of miR-29a in regulating cell cycle and angiogenic phenotype of endothelial cells. The results showed that miR-29a is highly expressed and upregulated by hypoxia-mimicking reagents in human umbilical vein endothelial cells (HUVEC). Consistent with this preliminary finding, introduction of exogenous agomiR-29a, or antagomir-29a altered cell cycle progression and promoted, or repressed the proliferation and tube formation of HUVEC, respectively. Furthermore, by using luciferase reporter assay, the expression of HBP1, a suppressor transcription factor was directly regulated by miR-29a through 3′-UTR. Increased or decreased HBP1 protein level was associated with the inhibition or overexpression of miR-29a, respectively. We conclude that miR-29a has a significant role in regulating cell cycle, proliferation and angiogenic properties of HUVEC, and this function is likely mediated through HBP1 protein at the post-transcriptional level. As a novel molecular target, miR-29a may have a potential value for the treatment of angiogenesis-associated diseases such as cardiovascular diseases and cancers.