MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer

Ri Cui, Wei Meng, Hui Lung Sun, Taewan Kim, Zhenqing Ye, Matteo Fassan, Young Jun Jeon, Bin Li, Caterina Vicentini, Yong Peng, Tae Jin Lee, Zhenghua Luo, Lan Liu, Dongyuan Xu, Esmerina Tili, Victor Jin, Justin Middleton, Arnab Chakravarti, Tim Lautenschlaeger, Carlo M. Croce

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identify microRNA-224 (miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. Increased miR-224 expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNFα-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated that miR-224 functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation of miR-224 expression in NSCLC. Up-regulated miR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targeting miR-224 could be effective in the treatment of certain lung cancer patients.

Original languageEnglish (US)
Pages (from-to)E4288-E4297
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number31
DOIs
StatePublished - Aug 4 2015

Keywords

  • Metastasis
  • MicroRNA
  • NSCLC
  • SMAD4
  • TNFAIP1

ASJC Scopus subject areas

  • General

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  • Cite this

    Cui, R., Meng, W., Sun, H. L., Kim, T., Ye, Z., Fassan, M., Jeon, Y. J., Li, B., Vicentini, C., Peng, Y., Lee, T. J., Luo, Z., Liu, L., Xu, D., Tili, E., Jin, V., Middleton, J., Chakravarti, A., Lautenschlaeger, T., & Croce, C. M. (2015). MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer. Proceedings of the National Academy of Sciences of the United States of America, 112(31), E4288-E4297. https://doi.org/10.1073/pnas.1502068112