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Authors
Shi, LeiMiddleton, J
Jeon, Y
Magee, Peter
Veneziano, D
Laganà, A
Leong, Hui Sun
Sahoo, Sudhakar
Fassan, M
Booton, R
Shah, R
Crosbie, P
Garofalo, Michela
Affiliation
Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UKIssue Date
2018-02-13
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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 DisJournal
Cell Death & DiseaseDOI
10.1038/s41419-017-0243-9PubMed ID
29440633Type
ArticleLanguage
enISSN
2041-4889ae974a485f413a2113503eed53cd6c53
10.1038/s41419-017-0243-9
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