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Tong Zhang,1–3 Wei Liu,4 Wei Meng,1–3 Hui Zhao,1–3 Qing Yang,1–3 Shi-jie Gu,1–3 Cui-cui Xiao,4 Chang-chang Jia,4 Bin-sheng Fu1–3 1Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Organ Transplantation Research Center of Guangdong Province, Guangzhou, People’s Republic of China; 4Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China Introduction: Hepatocellular carcinoma (HCC) accounts for more than 90% of primary liver cancer. Although great progress has been made on HCC molecular mechanism and therapy techniques, the prognosis of HCC patient is poor due to high metastasis and recurrence. Materials and methods: Expression of miR-542-3p was quantified by quantitative real-time PCR (qRT-PCR). The role of miR-542-3p in HCC metastasis was examined using transwell and 3D-culture assay. qRT-PCR, Western blotting and luciferase reporter assay were used to elucidate the mechanisms of miR-542-3p-mediated cancer metastasis.Results and Conclusion: In the research, we found that miR-542-3p is decreased in HCC cell lines and tissues, and downregulation of miR-542-3p enhances, while upregulation suppresses HCC cell invasion ability. Further assay demonstrated that miR-542-3p can directly target TGF-β1 3' untranslated region (3'UTR) to influence TGF-β/Smad signaling pathway, and suppression of miR-542-3p can hyperactivate TGF-β/Smad pathway and further to promote Epithelial-Mesenchyme Transition (EMT) and induce poor prognosis. Lastly, the clinical correlation analysis illustrated that miR-542-3p is negatively related with the activity of TGF-&a