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The miR-200 family and the miR-183~96~182 cluster target Foxf2 to inhibit invasion and metastasis in lung cancers

Oncogene volume 35, pages 173–186 (2016)Cite this article

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Abstract

Metastatic lung cancer is one of the most lethal forms of cancer and molecular pathways driving metastasis are still not clearly elucidated. Metastatic cancer cells undergo an epithelial–mesenchymal transition (EMT) where they lose their epithelial properties and acquire a migratory and invasive phenotype. Here we identify that the expression of microRNAs from the miR-200 family and the miR-183~96~182 cluster are significantly co-repressed in non-small cell lung cancer cell lines and primary tumors from multiple TCGA dataset with high EMT scores. Ectopic expression of the miR-183~96~182 cluster inhibited cancer cell migration and invasion, whereas its expression was tightly modulated by miR-200. We identified Foxf2 as a common, novel and direct target of both these microRNA families. Foxf2 expression tightly correlates with the transcription factor Zeb1 and is elevated in mesenchymal-like metastatic lung cancer cells. Foxf2 expression induced robust EMT, migration, invasion and metastasis in lung cancer cells, whereas Foxf2 inhibition significantly repressed these phenotypes. We also demonstrated that Foxf2 transcriptionally represses E-cadherin and miR-200, independent of Zeb1, to form a double-negative feedback loop. We, therefore, identified a novel mechanism whereby the miR-200 family and the miR-183~96~182 cluster inhibit lung cancer invasion and metastasis by targeting Foxf2.

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Acknowledgements

We thank Dr J. Larner (University of Virginia Health System, VA) for the kind gift of the pTRIPZ-GFP vector. We thank Dr G. Goodall (University of Adelaide, Australia) for the kind gift of the miR-200 promoter reporter construct.16 This work was supported by NCI K08 CA151661 (DLG), an MD Anderson Cancer Center Physician Scientist Award (DLG), Rexanna’s Foundation for Fighting Lung Cancer (DLG), a CDMRP Lung Cancer Research Program award W81XWH-12-10294 (DLG and STK). DP was supported by a CPRIT Graduate Scholar Training Grant (RP140106). LD, JW, PT are supported by Lung SPORE (P50 CA070907), Cancer Center Support Grant (CCSG CA016672) and Mary K. Chapman Foundation. CJC was supported by CPRIT grant RP120713 and NCI grant CA125123. DLG and LAB are R. Lee Clark Fellows of the University of Texas MD Anderson Cancer Center, supported by the Jeane F. Shelby Scholarship Fund. We would like to thank members of the Gibbons lab for the assistance and critical reading of the manuscript.

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  1. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S T Kundu, L A Byers, D H Peng, J D Roybal & D L Gibbons

  2. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    L Diao, J Wang, P Tong & C J Creighton

  3. Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    C J Creighton

  4. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    D L Gibbons

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Kundu, S., Byers, L., Peng, D. et al. The miR-200 family and the miR-183~96~182 cluster target Foxf2 to inhibit invasion and metastasis in lung cancers. Oncogene 35, 173–186 (2016). https://doi.org/10.1038/onc.2015.71

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