MicroRNA-199b-5p attenuates TGF-β1-induced epithelial–mesenchymal transition in hepatocellular carcinoma

Abstract

Background:Accumulating evidence indicates that N-cadherin is a cell adhesion molecule that has critical roles in tumour progression. However, the role of N-cadherin in hepatocellular carcinoma (HCC) remains controversial.Methods:This study aims to investigate the expression status of N-cadherin and its molecular mechanisms in HCC.Results:The expression of N-cadherin was markedly overexpressed in HCC tissues and cell lines. We identified that miR-199b-5p binds to the 3′-UTR of N-cadherin mRNA, thus decreasing N-cadherin expression in HCC cells. We also found the downregulation of miR-199b-5p in HCC specimens, which was inversely correlated with N-cadherin upregulation, predicted poor clinical outcomes in HCC patients. Next, we determined that miR-199b-5p overexpression promoted cell aggregation, suppressed cell migration and invasion in HCC cells, and inhibited xenografts tumour metastasis in nude mice. Moreover, we demonstrated that miR-199b-5p attenuated TGF-β1 induced epithelial–mesenchymal transition (EMT) -associated traits, while its effects could be partially reversed by N-cadherin restoration. Finally, we examined that N-cadherin downregulation or miR-199b-5p overexpression suppressed TGF-β1-induced Akt phosphorylation, and inhibition of PI3K/Akt pathway blocked TGF-β1-induced N-cadherin overexpression in HCC cells.Conclusions:Our data demonstrate that N-Cadherin was markedly overexpressed and miR-199b-5p was significantly downregulated in HCC. MiR-199b-5p exerts inhibitory effects on EMT, and directly targets N-cadherin in HCC, supporting the potential utility of miR-199b-5p as a promising strategy to treat HCC. Also, a positive regulatory loop exists between N-cadherin and Akt signalling represents a novel mechanism of TGF-β1-mediated EMT in HCC cells.

miR‐130a‐3p regulated TGF‐β1‐induced epithelial‐mesenchymal transition depends on SMAD4 in EC‐1 cells

“…Mengtao Ma et al found that MAGI2 promotes TGF‐β1‐induced EMT and migration and invasion of breast cancer cells under the direct action of miR‐487a . miR‐199b‐5p promotes cell aggregation, suppresses cell invasion and migration and inhibits TGF‐β‐induced EMT in hepatocellular carcinoma by inhibiting N‐cadherin . In several studies, miR‐130a‐3p was shown to decrease in cancer tissues and inhibit cell invasion, migration, and EMT .…”

NEAT1 upregulates TGF‐β1 to induce hepatocellular carcinoma progression by sponging hsa‐mir‐139‐5p

“…TGF-β1 can increase miR-155 and promote EMT, invasion and metastasis of HCC in vitro (Li, Wang, et al, 2017). miR-199b-5p can attenuate EMT in HCC by targeting TGF-β1 signal (Zhou et al, 2017). miR-663 overexpression can regulate HCC cell apoptosis through targeting TGF-β1 (Huang et al, 2016).…”

MicroRNA‑199b promotes cell proliferation and invasion in Wilms' tumour by directly targeting Runt‑related transcription factor 3

“…For instance, the miR-199b expression level is decreased in hepatocellular carcinoma. Hepatocellular carcinoma patients with low miR-199b levels show shorter overall survival and progression-free survival rates than those patients with high miR-199b levels (24,25). In bladder cancer, miR-199b expression is downregulated, which is associated with poor prognosis (26).…”

“…Nevertheless, miR-199b is found to play tumour suppressive roles in multiple human cancer types. For example, miR-199b overexpression suppresses cell proliferation and epithelial-mesenchymal transition, and increases radiosensitivity in hepatocellular carcinoma (24,25). Fang et al found that miR-199b overexpression restrains cell growth, colony formation and metastasis (27,28).…”

“…Several targets of miR-199b have previously been identified, including Hif1α (24) and N-cadherin (25) in hepatocellular carcinoma, HER2 (28) in breast cancer, SIRT1 (16) in colorectal cancer, ZEB1 (18) in non-small cell lung cancer and ITGA3 (30) in head and neck cancer. In this study, RUNX3 was proven to be a direct target of miR-199b in WT.…”