Li Yan, Xu Dan, Bao Chunyang, Zhang Yuannv, Chen Di, Zhao Fangyu, Ding Jie, Liang Linhui, Wang Qifeng, Liu Li, Li Jinjun, Yao Ming, Huang Shenglin, He Xianghuo
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Oncotarget. 2015 Feb 10;6(4):2421-33. doi: 10.18632/oncotarget.2965.
MicroRNAs (miRNAs) often localize to chromosomal fragile sites and are associated with cancer. In this study, we screened for the aberrant and functional miRNAs in the regions of copy number alterations (CNAs) in hepatocellular carcinoma (HCC), and found that miR-135b was frequently amplified and upregulated in HCC tissues. The expression level of miR-135b was inversely correlated with the occurrence of tumor capsules. In addition, miR-135b promoted HCC cell migration and invasion in vitro and metastasis in vivo. The reversion-inducing-cysteine-rich protein with kazal motifs (RECK) and ecotropic viral integration site 5 (EVI5) were identified as the direct and functional targets of miR-135b in HCC. Furthermore, we observed that heat shock transcription factor 1 (HSF1) directly activated miR-135b expression, consequently enhancing HCC cell motility and invasiveness. The newly identified HSF1/miR-135b/RECK&EVI5 axis provides novel insight into the mechanisms of HCC metastasis, which may facilitate the development of new therapeutics against HCC.
微小RNA（miRNA）常常定位于染色体脆弱位点并与癌症相关。在本研究中，我们筛查了肝细胞癌（HCC）中拷贝数改变（CNA）区域内异常且具有功能的miRNA，发现miR-135b在HCC组织中经常扩增且上调。miR-135b的表达水平与肿瘤包膜的形成呈负相关。此外，miR-135b在体外促进HCC细胞迁移和侵袭，在体内促进转移。富含kazal基序的逆转诱导富含半胱氨酸蛋白（RECK）和嗜异性病毒整合位点5（EVI5）被确定为miR-135b在HCC中的直接且具有功能的靶点。此外，我们观察到热休克转录因子1（HSF1）直接激活miR-135b的表达，从而增强HCC细胞的运动性和侵袭性。新发现的HSF1/miR-135b/RECK&EVI5轴为HCC转移机制提供了新的见解，这可能有助于开发针对HCC的新疗法。
