New tumor suppressor microRNAs target glypican-3 in human liver cancer.
New tumor suppressor microRNAs target glypican-3 in human liver cancer.
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DOI：
10.18632/oncotarget.17162
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发表时间：
2017-06-20
期刊：
影响因子：
--
通讯作者：
Grosset CF
中科院分区：
文献类型：
--
作者：
Cartier F;Indersie E;Lesjean S;Charpentier J;Hooks KB;Ghousein A;Desplat A;Dugot-Senant N;Trézéguet V;Sagliocco F;Hagedorn M;Grosset CF
Glypican-3 （GPC3）是一种致癌基因，在肝细胞癌（HCC）和肝母细胞瘤等肝脏恶性肿瘤中经常上调，是肝癌治疗的潜在分子靶点。通过功能筛选系统，我们在恶性肝细胞中发现了10个新的控制GPC3表达的microrna，其中miR-4510、miR-203a-3p、miR-548aa、miR-376b-3p和miR-548v 5个microrna可降低GPC3的表达。与非肿瘤肝脏相比，这5种microrna在肿瘤肝脏中显著下调，抑制肿瘤细胞的增殖。有趣的是，在HCC样本中，miR-4510与GPC3 mRNA和蛋白呈负相关。在鸡绒毛膜尿囊膜模型中，该microRNA还能诱导肝癌细胞凋亡并抑制肿瘤生长。我们进一步证明miR-4510的肿瘤抑制作用是通过直接靶向GPC3 mRNA和Wnt/β-catenin转录活性和信号通路失活介导的。此外，miR-4510上调了几种肿瘤抑制基因的表达，同时降低了其他癌前基因的表达。总之，我们发现了几个新的靶向GPC3致癌功能的microrna。我们为miR-4510的肿瘤抑制活性提供了强有力的分子、细胞和体内证据，从而突出了该microRNA在HCC治疗中的潜在价值。
Glypican-3 (GPC3) is an oncogene, frequently upregulated in liver malignancies such as hepatocellular carcinoma (HCC) and hepatoblastoma and constitutes a potential molecular target for therapy in liver cancer. Using a functional screening system, we identified 10 new microRNAs controlling GPC3 expression in malignant liver cells, five of them e.g. miR-4510, miR-203a-3p, miR-548aa, miR-376b-3p and miR-548v reduce GPC3 expression. These 5 microRNAs were significantly downregulated in tumoral compared to non-tumoral liver and inhibited tumor cell proliferation. Interestingly, miR-4510 inversely correlated with GPC3 mRNA and protein in HCC samples. This microRNA also induced apoptosis of hepatoma cells and blocked tumor growth in vivo in the chick chorioallantoic membrane model. We further show that the tumor suppressive effect of miR-4510 is mediated through direct targeting of GPC3 mRNA and inactivation of Wnt/β-catenin transcriptional activity and signaling pathway. Moreover, miR-4510 up-regulated the expression of several tumor suppressor genes while reducing the expression of other pro-oncogenes. In summary, we uncovered several new microRNAs targeting the oncogenic functions of GPC3. We provided strong molecular, cellular and in vivo evidences for the tumor suppressive activities of miR-4510 bringing to the fore the potential value of this microRNA in HCC therapy.
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