ADAM9 enhances CDCP1 protein expression by suppressing miR-218 for lung tumor metastasis.
ADAM9 enhances CDCP1 protein expression by suppressing miR-218 for lung tumor metastasis.
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DOI：
10.1038/srep16426
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发表时间：
2015-11-10
影响因子：
4.6
通讯作者：
Sher YP
中科院分区：
文献类型：
--
作者：
Chiu KL;Kuo TT;Kuok QY;Lin YS;Hua CH;Lin CY;Su PY;Lai LC;Sher YP
转移是癌症患者死亡的主要原因，因为难以控制这个复杂的过程。微小RNA（microRNA，miRNA）是一种内源性非编码短RNA，具有重要的生物学和病理学功能，可能在肿瘤转移过程中发挥调控作用，但其作用机制尚未完全阐明。我们以前证明，ADAM 9增强了促迁移蛋白CDCP 1的表达，以促进肺转移;然而，调控过程仍然未知。在这里，我们证明了内源性miR-218，这是丰富的正常肺组织，但在肺肿瘤抑制，在ADAM 9介导的CDCP 1表达的过程中进行调节。miR-218的抑制与肺癌细胞的高迁移能力相关。在基于内切酶的转录报告基因分析中检测到miR-218与CDCP 1 mRNAs的3′-UTR之间的直接相互作用。CDCP 1蛋白水平随着miR-218表达水平的增加而降低，并且在用miR-218 miR-218处理的细胞中增加。miR-218的诱导在体外抑制肿瘤细胞移动性、无锚定存活和肿瘤起始细胞形成，并延迟小鼠中的肿瘤转移。我们的研究结果揭示了miR-218在肺癌发生和转移中的综合肿瘤抑制功能。
Metastasis is the leading cause of death in cancer patients due to the difficulty of controlling this complex process. MicroRNAs (miRNA), endogenous noncoding short RNAs with important biological and pathological functions, may play a regulatory role during cancer metastasis, but this role has yet to be fully defined. We previously demonstrated that ADAM9 enhanced the expression of the pro-migratory protein CDCP1 to promote lung metastasis; however, the regulatory process remains unknown. Here we demonstrate that endogenous miR-218, which is abundant in normal lung tissue but suppressed in lung tumors, is regulated during the process of ADAM9-mediated CDCP1 expression. Suppression of miR-218 was associated with high migration ability in lung cancer cells. Direct interaction between miR-218 and the 3′-UTR of CDCP1 mRNAs was detected in luciferase-based transcription reporter assays. CDCP1 protein levels decreased as expression levels of miR-218 increased, and increased in cells treated with miR-218 antagomirs. Induction of miR-218 inhibited tumor cell mobility, anchorage-free survival, and tumor-initiating cell formation in vitro and delayed tumor metastases in mice. Our findings revealed an integrative tumor suppressor function of miR-218 in lung carcinogenesis and metastasis.