Fang Feng, Song Tianqiang, Zhang Ti, Cui Yunlong, Zhang Gewen, Xiong Qingqing
Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, Ti-Yuan-Bei, Tianjin 300060, China.
Department of Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
Oncotarget. 2017 May 9;8(19):31745-31757. doi: 10.18632/oncotarget.15958.
MicroRNAs (miRNAs) play critical roles in hepatocellular carcinoma (HCC) progression and are key determinants of prognosis. In this study, we found that miR-425-5p was elevated in HCC and correlated with poor prognostic clinicopathological features and low post-operative long-term survival. Multivariate survival analysis indicated that miR-425-5p expression was an independent risk factor for overall and disease-free survival. Interestingly, miR-425-5p promoted invasion and metastasis by HCC cells, but not HCC cell proliferation or apoptosis in vitro. SCAI and PTEN were determined to be downstream targets of miR-425-5p. miR-425-5p-mediated effects were inhibited by ectopic expression of SCAI, and PTEN exhibited a smaller inhibitory effect. SCAI also suppressed PTEN expression. In addition, miR-425-5p promoted epithelial-to-mesenchymal transition (EMT), which was antagonized by SCAI. miR-425-5p also promoted HCC cell invasion and metastasis via SCAI-mediated dysregulation of integrin β1-Fak/Src-RhoA/CDC42, PTEN-AKT, and TIMP2-MMP2/MMP9 signaling. Finally, miR-425-5p promoted metastasis in a xenograft mouse model of HCC. These results indicate that miR-425-5p facilitates EMT and extracellular matrix degradation and promotes HCC metastasis through SCAI-mediated dysregulation of multiple signaling pathways. MiR-425-5p is therefore a potential prognostic biomarker and novel therapeutic target in HCC.
微小RNA（miRNA）在肝细胞癌（HCC）进展中发挥关键作用，是预后的关键决定因素。在本研究中，我们发现miR-425-5p在HCC中表达升高，且与不良预后的临床病理特征及术后低长期生存率相关。多因素生存分析表明，miR-425-5p表达是总生存和无病生存的独立危险因素。有趣的是，miR-425-5p促进HCC细胞的侵袭和转移，但在体外不影响HCC细胞增殖或凋亡。SCAI和PTEN被确定为miR-425-5p的下游靶点。SCAI的异位表达抑制了miR-425-5p介导的效应，而PTEN的抑制作用较小。SCAI还抑制PTEN表达。此外，miR-425-5p促进上皮-间质转化（EMT），而SCAI可拮抗这一过程。miR-425-5p还通过SCAI介导的整合素β1-Fak/Src-RhoA/CDC42、PTEN-AKT和TIMP2-MMP2/MMP9信号通路失调促进HCC细胞侵袭和转移。最后，miR-425-5p在HCC异种移植小鼠模型中促进转移。这些结果表明，miR-425-5p通过SCAI介导的多条信号通路失调促进EMT和细胞外基质降解，进而促进HCC转移。因此，miR-425-5p是HCC潜在的预后生物标志物和新的治疗靶点。
