ADAM9 enhances CDCP1 by inhibiting miR-1 through EGFR signaling activation in lung cancer metastasis

Kuo Liang Chiu, Yu Sen Lin, Ting Ting Kuo, Chia Chien Lo, Yu Kai Huang, Hsien Fang Chang, Eric Y. Chuang, Ching Chan Lin, Wei Chung Cheng, Yen Nien Liu, Liang Chuan Lai, Yuh Pyng Sher

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)47365-47378
Number of pages14
JournalOncotarget
Volume8
Issue number29
DOIs
Publication statusPublished - 2017

Keywords

  • ADAM9
  • CDCP1
  • EGFR
  • Lung cancer
  • MiR-1

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Chiu, K. L., Lin, Y. S., Kuo, T. T., Lo, C. C., Huang, Y. K., Chang, H. F., Chuang, E. Y., Lin, C. C., Cheng, W. C., Liu, Y. N., Lai, L. C., & Sher, Y. P. (2017). ADAM9 enhances CDCP1 by inhibiting miR-1 through EGFR signaling activation in lung cancer metastasis. Oncotarget, 8(29), 47365-47378. https://doi.org/10.18632/oncotarget.17648