microRNA-489 Plays an Anti-Metastatic Role in Human Hepatocellular Carcinoma by Targeting Matrix Metalloproteinase-7.
microRNA-489 Plays an Anti-Metastatic Role in Human Hepatocellular Carcinoma by Targeting Matrix Metalloproteinase-7.
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DOI：
10.1016/j.tranon.2017.01.010
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发表时间：
2017-04
影响因子：
5
通讯作者：
Kan H
中科院分区：
文献类型：
--
作者：
Lin Y;Liu J;Huang Y;Liu D;Zhang G;Kan H
microRNAs （miRNAs）的失调在肝细胞癌（HCC）的发病和致瘤性中起着积极的作用。miR-489被发现在人类癌症中发挥致癌或肿瘤抑制作用。近期研究报道，miR-489在HCC晚期复发患者中的表达水平明显高于早期复发患者，提示miR-489可能在HCC中发挥抑瘤miRNA的作用。然而，miR-489在HCC中的临床价值和生物学功能尚不清楚。在这里，我们提出HCC组织中的miR-489水平与匹配的非癌标本相比显着降低。其水平的降低与HCC患者的不良临床参数和不良预后明显相关。因此，在HCC细胞中miR-489水平明显下调。在HCCLM3和MHCC97H细胞中异位表达miR-489显著抑制肿瘤细胞的迁移和侵袭，减少体内肺转移，而miR-489敲低则增加HepG2和MHCC97L细胞的这些行为。机械地，miR-489负调控HCC细胞中基质金属蛋白酶-7 （MMP7）的丰度。本研究发现MMP7是HCC中miR-489的下游分子。在HCC标本中证实miR-489与MMP7呈负相关。MMP7敲低抑制细胞迁移和侵袭，而MMP7过表达对HCC细胞的影响相反。此外，恢复MMP7的表达可以消除miR-489对HCCLM3细胞的抗转移作用，增强细胞的迁移和侵袭。总之，miR-489可能作为HCC患者的预后预测因子和药物靶点。
Dysregulation of microRNAs (miRNAs) is actively involved in the pathogenesis and tumorigenicity of hepatocellular carcinoma (HCC). miR-489 was found to play either oncogenic or tumor suppressive roles in human cancers. Recent study reported that the levels of miR-489 in late recurrent HCC patients were evidently higher than that in early recurrent cases, suggesting that miR-489 may function as a tumor suppressive miRNA in HCC. Yet, the clinical value and biological function of miR-489 remain rarely known in HCC. Here, we presented that miR-489 level in HCC tissues was notably reduced compared to matched non-cancerous specimens. Its decreased level was evidently correlated with adverse clinical parameters and poor prognosis of HCC patients. Accordingly, the levels of miR-489 were obviously down-regulated in HCC cells. Ectopic expression of miR-489 in HCCLM3 and MHCC97H cells prominently inhibits the migration and invasion of tumor cells and reduced lung metastases in vivo, while miR-489 knockdown increased these behaviors of HepG2 and MHCC97L cells. Mechanically, miR-489 negatively regulated matrix metalloproteinase-7 (MMP7) abundance in HCC cells. Herein, MMP7 was found to be a downstream molecule of miR-489 in HCC. An inversely correlation between miR-489 and MMP7 was confirmed in HCC specimens. MMP7 knockdown prohibited cell migration and invasion while MMP7 overexpression showed opposite effects on HCC cells. Furthermore, restoration of MMP7 expression could abrogate the anti-metastatic effects of miR-489 on HCCLM3 cells with enhanced cell migration and invasion. Altogether, miR-489 potentially acts as a prognostic predictor and a drug-target for HCC patients.