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MicroRNA-148a suppresses the epithelial–mesenchymal transition and metastasis of hepatoma cells by targeting Met/Snail signaling

Oncogene volume 33, pages 4069–4076 (2014)Cite this article

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Abstract

Metastasis is responsible for the rapid recurrence and poor survival of malignancies. Epithelial–mesenchymal transition (EMT) has a critical role in metastasis. Increasing evidence indicates that EMT can be regulated by microRNAs (miRNAs). miR-148a is a liver-abundant miRNA. However, the role of miR-148a in the development of liver cancer remains largely unknown. In this study, we found that, compared with normal livers, miR-148a was significantly decreased in hepatocellular carcinoma (HCC) tissues, especially in those with the portal vein tumor thrombus. An in vitro transwell assay and an in vivo orthotopic liver xenograft model showed that the restoration of miR-148a expression significantly repressed the migration and pulmonary metastasis of hepatoma cells. Linear regression analysis revealed a positive correlation between the expression of miR-148a and the mRNA level of E-cadherin gene in human HCC tissues. Both gain- and loss-of-function studies disclosed that miR-148a promoted the expression of epithelial marker (E-cadherin) and reduced the levels of mesenchymal markers (N-cadherin, fibronectin or vimentin) in hepatoma cells. These data suggest that miR-148a may suppress EMT and cancer metastasis. Further mechanistic investigations showed that miR-148a directly inhibited Met expression by binding to its 3′-UTR. Moreover, the reintroduction of miR-148a attenuated the downstream signaling of Met, like activated phosphorylation of AKT-Ser473 and inhibitory phosphorylation of GSK-3β-Ser9, and consequently reduced the nuclear accumulation of Snail, a transcription factor that promotes EMT. Taken together, miR-148a may negatively regulate Met/Snail signaling and therefore inhibit the EMT and metastasis of hepatoma cells. These findings highlight the significance of miR-148a downregulation in tumor progression and implicate miR-148a as an attractive candidate for cancer therapy.

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Acknowledgements

This study was supported by grants from Ministry of Science and Technology of China (2010CB912803, 2011CB811305), Ministry of Health of China (2012ZX10002011), National Natural Science Foundation of China (81101593, 30925036), Ministry of Education of China (20110171120043).

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  1. J-P Zhang, C Zeng and L Xu: These authors contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, People’s Republic of China

    J-P Zhang, C Zeng, J Gong, J-H Fang & S-M Zhuang

  2. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, People’s Republic of China

    J-P Zhang & L Xu

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  1. J-P Zhang
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Correspondence to S-M Zhuang.

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Zhang, JP., Zeng, C., Xu, L. et al. MicroRNA-148a suppresses the epithelial–mesenchymal transition and metastasis of hepatoma cells by targeting Met/Snail signaling. Oncogene 33, 4069–4076 (2014). https://doi.org/10.1038/onc.2013.369

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