Chiu Kuo-Liang, Lin Yu-Sen, Kuo Ting-Ting, Lo Chia-Chien, Huang Yu-Kai, Chang Hsien-Fang, Chuang Eric Y, Lin Ching-Chan, Cheng Wei-Chung, Liu Yen-Nien, Lai Liang-Chuan, Sher Yuh-Pyng
Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.
Division of Chest Medicine, Department of Internal Medicine, Taichung Tzu-Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan.
Oncotarget. 2017 Jul 18;8(29):47365-47378. doi: 10.18632/oncotarget.17648.
MicroRNAs (miRNAs), which are endogenous short noncoding RNAs, can regulate genes involved in important biological and pathological functions. Therefore, dysregulation of miRNAs plays a critical role in cancer progression. However, whether the aberrant expression of miRNAs is regulated by oncogenes remains unclear. We previously demonstrated that a disintegrin and metalloprotease domain 9 (ADAM9) promotes lung metastasis by enhancing the expression of a pro-migratory protein, CUB domain containing protein 1 (CDCP1). In this study, we found that this process occurred via miR-1 down-regulation. miR-1 expression was down-regulated in lung tumors, but increased in ADAM9-knockdown lung cancer cells, and was negatively correlated with CDCP1 expression as well as the migration ability of lung cancer cells. Luciferase-based reporter assays showed that miR-1 directly bound to the 3'-untranslated region of CDCP1 and inhibited its translation. Treatment with a miR-1 inhibitor restored CDCP1 protein levels and enhanced tumor cell mobility. Overexpression of miR-1 decreased tumor metastases and increased the survival rate in mice. ADAM9 knockdown reduced EGFR signaling and increased miR-1 expression. These results revealed that ADAM9 down-regulates miR-1 via activating EGFR signaling pathways, which in turn enhances CDCP1 expression to promote lung cancer progression.
微小RNA（miRNA）是内源性短链非编码RNA，可调控参与重要生物学和病理学功能的基因。因此，miRNA的失调在癌症进展中起关键作用。然而，miRNA的异常表达是否受癌基因调控仍不清楚。我们先前证明，去整合素和金属蛋白酶结构域9（ADAM9）通过增强促迁移蛋白含CUB结构域蛋白1（CDCP1）的表达来促进肺转移。在本研究中，我们发现这一过程是通过miR-1下调发生的。miR-1在肺肿瘤中表达下调，但在ADAM9敲低的肺癌细胞中升高，且与CDCP1表达以及肺癌细胞的迁移能力呈负相关。基于荧光素酶的报告基因检测表明，miR-1直接与CDCP1的3'非翻译区结合并抑制其翻译。用miR-1抑制剂处理可恢复CDCP1蛋白水平并增强肿瘤细胞迁移能力。miR-1的过表达减少了肿瘤转移并提高了小鼠的存活率。ADAM9敲低降低了表皮生长因子受体（EGFR）信号传导并增加了miR-1表达。这些结果表明，ADAM9通过激活EGFR信号通路下调miR-1，进而增强CDCP1表达以促进肺癌进展。
