Huang Bin, Huang Manping, Li Qin
Department of Intervention, Hunan Provincial Cancer Hospital, Changsha 410009, PR China.
Department of Gynecology, Affiliated Hospital of Hunan Institute of Traditional Chinese Medicine, Changsha 410009, PR China.
Pathol Res Pract. 2018 Dec;214(12):1980-1986. doi: 10.1016/j.prp.2018.08.005. Epub 2018 Aug 8.
Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies and many cell-intrinsic identities and extrinsic epigenetic factors influence the metastatic potential of HCC cells. MicroRNA-137 is often found to be acting as tumor suppressors, however, how miR-137 involved in the metastasis progression in human HCC remains unclear.
QPCR was performed to detect the miR-137 mRNA levels in HCC cell linesand normal liver cell line HL7702.Then transwell assay and wound-healing assay were determined to investigate the motility of HCC cells introduced into lentivirus to ectopically upregulate endogenous miR-137 and EAH2 expressions. Targeting of enhancer of zeste homolog 2 (EZH2) gene by miR-137 in HCC was assessed by dual-luciferase activity assay and qPCR. Western blot was applied to explore the mechanism. In vivo, lung metastasis were evaluated using a mice tail vein injection model.
In this study, we found that miR-137 is decreased in HCC cell lines and had an inhibitory effect on HCC migration and invasion in vitro. EZH2 was a direct downstream target gene of miR-137 in HCC and miR-137 suppressed invasion and migration by targeting EZH2-STAT3 signaling in HCC cells. Furthermore, EZH2 overexpression reversed the miR-137 mimics-induced inhibitory effects on migration and invasion of HCC cells. In addition, miR-137 inhibited lung metastasis of HCC in vivo by targeting EZH2-STAT3 signaling.
MiR-137 suppressed migration and invasion by targeting EZH2-STAT3 signaling pathway in HCC cells in vitro and in vivo, suggesting miR-137-EZH2-STAT3 may be a potential therapeutic target for treatment of human hepatocellular carcinoma.
肝细胞癌（HCC）是最常见且侵袭性最强的人类恶性肿瘤之一，许多细胞内在特性和外在表观遗传因素会影响HCC细胞的转移潜能。MicroRNA-137通常被发现具有肿瘤抑制作用，然而，miR-137如何参与人类HCC的转移进展仍不清楚。
采用QPCR检测HCC细胞系和正常肝细胞系HL7702中miR-137的mRNA水平。然后通过Transwell实验和伤口愈合实验来研究导入慢病毒以异位上调内源性miR-137和EAH2表达后HCC细胞的运动能力。通过双荧光素酶活性测定和qPCR评估miR-137在HCC中对zeste同源物2（EZH2）基因的靶向作用。应用蛋白质免疫印迹法探究其机制。在体内，使用小鼠尾静脉注射模型评估肺转移情况。
在本研究中，我们发现miR-137在HCC细胞系中表达降低，并且对体外HCC的迁移和侵袭具有抑制作用。EZH2是HCC中miR-137的直接下游靶基因，miR-137通过靶向HCC细胞中的EZH2-STAT3信号通路抑制侵袭和迁移。此外，EZH2过表达逆转了miR-137模拟物对HCC细胞迁移和侵袭的抑制作用。另外，miR-137在体内通过靶向EZH2-STAT3信号通路抑制HCC的肺转移。
miR-137在体外和体内均通过靶向HCC细胞中的EZH2-STAT3信号通路抑制迁移和侵袭，提示miR-137-EZH2-STAT3可能是治疗人类肝细胞癌的潜在治疗靶点。
