Downregulation of microRNA-100 enhances the ICMT-Rac1 signaling and promotes metastasis of hepatocellular carcinoma cells
Downregulation of microRNA-100 enhances the ICMT-Rac1 signaling and promotes metastasis of hepatocellular carcinoma cells
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DOI：
10.18632/oncotarget.2601
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发表时间：
2014-10
期刊：
影响因子：
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通讯作者：
Hui-Chao Zhou;Jian-Hong Fang;Xuan Luo;Lei Zhang;Jin-E Yang;Chong Zhang;Shi‐Mei Zhuang
中科院分区：
文献类型：
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作者：
Hui-Chao Zhou;Jian-Hong Fang;Xuan Luo;Lei Zhang;Jin-E Yang;Chong Zhang;Shi‐Mei Zhuang
转移是肝细胞癌（HCC）快速复发和HCC患者生存差的原因。本研究表明，HCC组织中miR-100下调与静脉侵袭、TNM晚期、肿瘤结节无完整囊、细胞分化较差、无复发生存期较短显著相关。功能获得和功能丧失研究均表明，miR-100在体外显著抑制HCC细胞通过基质细胞迁移和侵袭的能力。小鼠原位异种移植模型分析进一步显示，与对照组相比，稳定表达mir -100的肝癌细胞异种移植的肺转移率显著降低。随后的研究发现，miR-100通过结合异戊酰半胱氨酸羧基甲基转移酶（ICMT）和ras相关的C3肉毒毒素底物1 （Rac1）的3′- utr直接抑制其表达，进而抑制板足形成和基质金属肽酶2 （MMP2）的激活。此外，ICMT和Rac1的下调可表型化miR-100的抗转移作用，而组成活性的Rac1 （Q61L）的过表达可拮抗miR-100的功能。综上所述，miR-100通过消除ICMT-Rac1信号传导抑制HCC细胞的转移。miR-100的下调有助于HCC转移，miR-100的恢复是癌症治疗的潜在策略。
Metastasis is responsible for rapid recurrence of hepatocellular carcinoma (HCC) and poor survival of HCC patients. Here we showed that miR-100 downregulation in HCC tissues was significantly associated with venous invasion, advanced TNM stage, tumor nodule without complete capsule, poorer cell differentiation, and shorter recurrence-free survival. Both gain- and loss-of-function studies showed that miR-100 dramatically suppressed the ability of HCC cells to migrate and to invade through Matrigel in vitro. Analyses using mouse orthotopic xenograft model further revealed that xenografts of miR-100-stable-expressing HCC cells displayed a significant reduction in pulmonary metastasis, compared with control group. Subsequent investigations revealed that miR-100 directly inhibited the expression of isoprenylcysteine carboxyl methyltransferase (ICMT) and ras-related C3 botulinum toxin substrate 1 (Rac1) by binding to their 3′-UTRs, and in turn suppressed lamellipodia formation and matrix metallopeptidase 2 (MMP2) activation. Furthermore, knockdown of ICMT and Rac1 phenocopied the anti-metastasis effect of miR-100, whereas overexpression of the constitutively active Rac1 (Q61L) antagonized the function of miR-100. Taken together, miR-100 represses metastasis of HCC cells by abrogating the ICMT-Rac1 signaling. Downregulation of miR-100 contributes to HCC metastasis and the restoration of miR-100 is a potential strategy for cancer therapy.