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    KRAS induces lung tumorigenesis through microRNAs modulation.

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    Authors
    Shi, Lei
    Middleton, J
    Jeon, Y
    Magee, Peter
    Veneziano, D
    Laganà, A
    Leong, Hui Sun
    Sahoo, Sudhakar
    Fassan, M
    Booton, R
    Shah, R
    Crosbie, P
    Garofalo, Michela
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    Affiliation
    Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK
    Issue Date
    2018-02-13
    
    Metadata
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    Abstract
    Oncogenic KRAS induces tumor onset and development by modulating gene expression via different molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that have been established as main players in tumorigenesis. By overexpressing wild type or mutant KRAS (KRASG12D) and using inducible human and mouse cell lines, we analyzed KRAS-regulated microRNAs in non-small-cell lung cancer (NSCLC). We show that miR-30c and miR-21 are significantly upregulated by both KRAS isoforms and induce drug resistance and enhance cell migration/invasion via inhibiting crucial tumor suppressor genes, such as NF1, RASA1, BID, and RASSF8. MiR-30c and miR-21 levels were significantly elevated in tumors from patients that underwent surgical resection of early stages NSCLC compared to normal lung and in plasma from the same patients. Systemic delivery of LNA-anti-miR-21 in combination with cisplatin in vivo completely suppressed the development of lung tumors in a mouse model of lung cancer. Mechanistically, we demonstrated that ELK1 is responsible for miR-30c and miR-21 transcriptional activation by direct binding to the miRNA proximal promoter regions. In summary, our study defines that miR-30c and miR-21 may be valid biomarkers for early NSCLC detection and their silencing could be beneficial for therapeutic applications.
    Citation
    KRAS induces lung tumorigenesis through microRNAs modulation. 2018, 9 (2):219 Cell Death Dis
    Journal
    Cell Death & Disease
    URI
    http://hdl.handle.net/10541/620833
    DOI
    10.1038/s41419-017-0243-9
    PubMed ID
    29440633
    Type
    Article
    Language
    en
    ISSN
    2041-4889
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41419-017-0243-9
    Scopus Count
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    All Paterson Institute for Cancer Research

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