Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.
Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.
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Hsa-miR-623抑制人肺腺癌的肿瘤进展。
DOI：
10.1038/cddis.2016.260
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发表时间：
2016-09-29
影响因子：
9
通讯作者：
Xiong WN
中科院分区：
文献类型：
--
作者：
Wei S;Zhang ZY;Fu SL;Xie JG;Liu XS;Xu YJ;Zhao JP;Xiong WN
我们前期研究发现Ku80在肺癌组织中过表达，hsa-miR-623对Ku80表达有调控作用；然而，hsa-miR-623在肺癌中的详细功能尚不清楚。我们发现 hsa-miR-623 与 Ku80 mRNA 的 3'-UTR 结合，从而显着降低肺腺癌细胞中 Ku80 的表达。与相应的非肿瘤组织相比，HSA-miR-623在肺腺癌组织中表达下调，且其表达与Ku80的上调呈负相关。 hsa-miR-623 的下调与肺腺癌患者的不良临床结果相关。 Hsa-miR-623 在体外抑制肺腺癌细胞增殖、克隆形成、迁移和侵袭。 Hsa-miR-623 抑制体内肺腺癌异种移植物的生长和转移。肺腺癌细胞中 Ku80 敲低在体外和体内抑制肿瘤特性，类似于 hsa-miR-623 过表达。此外，hsa-miR-623 过表达降低了基质金属蛋白酶-2 (MMP-2) 和 MMP-9 的表达水平，并降低了 ERK/JNK 磷酸化。抑制hsa-miR-623或过度表达Ku80可促进肺腺癌细胞侵袭，激活ERK/JNK磷酸化并增加MMP-2/9表达，而ERK激酶抑制剂或JNK激酶抑制剂可以逆转这种情况。总之，我们的结果表明，hsa-miR-623在肺腺癌中下调，并通过ERK/JNK失活介导的MMP-2/9下调抑制针对Ku80的侵袭和转移。这些发现表明 hsa-miR-623 可能作为肺癌治疗的重要治疗靶点。
Our previous study revealed that Ku80 was overexpressed in lung cancer tissues and hsa-miR-623 regulated the Ku80 expression; however, the detailed function of hsa-miR-623 in lung cancer was unclear. We identified that hsa-miR-623 bound to the 3'-UTR of Ku80 mRNA, thus significantly decreasing Ku80 expression in lung adenocarcinoma cells. Hsa-miR-623 was downregulated in lung adenocarcinoma tissues compared with corresponding non-tumorous tissues, and its expression was inversely correlated with Ku80 upregulation. Downregulation of hsa-miR-623 was associated with poor clinical outcomes of lung adenocarcinoma patients. Hsa-miR-623 suppressed lung adenocarcinoma cell proliferation, clonogenicity, migration and invasion in vitro. Hsa-miR-623 inhibited xenografts growth and metastasis of lung adenocarcinoma in vivo. Ku80 knockdown in lung adenocarcinoma cells suppressed tumor properties in vitro and in vivo similar to hsa-miR-623 overexpression. Further, hsa-miR-623 overexpression decreased matrix metalloproteinase-2 (MMP-2) and MMP-9 expression levels, with decreased ERK/JNK phosphorylation. Inhibition of hsa-miR-623 or overexpression of Ku80 promoted lung adenocarcinoma cell invasion, activated ERK/JNK phosphorylation and increased MMP-2/9 expressions, which could be reversed by ERK kinase inhibitor or JNK kinase inhibitor. In summary, our results showed that hsa-miR-623 was downregulated in lung adenocarcinoma and suppressed the invasion and metastasis targeting Ku80 through ERK/JNK inactivation mediated downregulation of MMP-2/9. These findings reveal that hsa-miR-623 may serve as an important therapeutic target in lung cancer therapy.
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