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MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells
Non-small cell lung cancers (NSCLCs) that harbor an oncogenic KRAS mutation are often associated with resistance to targeted therapies. The MUC1-C transmembrane protein is aberrantly overexpressed in NSCLCs and confers a poor outcome; however, the functional role for MUC1-C in mutant KRAS NSCLC cell...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253405/ https://www.ncbi.nlm.nih.gov/pubmed/25245423 |
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author | Kharbanda, Akriti Rajabi, Hasan Jin, Caining Alam, Maroof Wong, Kwok-Kin Kufe, Donald |
author_facet | Kharbanda, Akriti Rajabi, Hasan Jin, Caining Alam, Maroof Wong, Kwok-Kin Kufe, Donald |
author_sort | Kharbanda, Akriti |
collection | PubMed |
description | Non-small cell lung cancers (NSCLCs) that harbor an oncogenic KRAS mutation are often associated with resistance to targeted therapies. The MUC1-C transmembrane protein is aberrantly overexpressed in NSCLCs and confers a poor outcome; however, the functional role for MUC1-C in mutant KRAS NSCLC cells has remained unclear. The present studies demonstrate that silencing MUC1-C in A549/KRAS(G12S) and H460/KRAS(Q61H) NSCLC cells is associated with downregulation of AKT signaling and inhibition of growth. Overexpression of a MUC1-C(CQC→AQA) mutant, which inhibits MUC1-C homodimerization and function, suppressed both AKT and MEK activation. Moreover, treatment with GO-203, an inhibitor of MUC1-C homodimerization, blocked AKT and MEK signaling and decreased cell survival. The results further demonstrate that targeting MUC1-C suppresses expression of the ZEB1 transcriptional repressor by an AKT-mediated mechanism, and in turn induces miR-200c. In concert with these effects on the ZEB1/miR-200c regulatory loop, targeting MUC1-C was associated with reversal of the epithelial-mesenchymal transition (EMT) and inhibition of self-renewal capacity. Loss of MUC1-C function also attenuated KRAS independence and inhibited growth of KRAS mutant NSCLC cells as tumors in mice. These findings support a model in which targeting MUC1-C inhibits mutant KRAS signaling in NSCLC cells and thereby reverses the EMT phenotype and decreases self-renewal. |
format | Online Article Text |
id | pubmed-4253405 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-42534052014-12-03 MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells Kharbanda, Akriti Rajabi, Hasan Jin, Caining Alam, Maroof Wong, Kwok-Kin Kufe, Donald Oncotarget Priority Research Paper Non-small cell lung cancers (NSCLCs) that harbor an oncogenic KRAS mutation are often associated with resistance to targeted therapies. The MUC1-C transmembrane protein is aberrantly overexpressed in NSCLCs and confers a poor outcome; however, the functional role for MUC1-C in mutant KRAS NSCLC cells has remained unclear. The present studies demonstrate that silencing MUC1-C in A549/KRAS(G12S) and H460/KRAS(Q61H) NSCLC cells is associated with downregulation of AKT signaling and inhibition of growth. Overexpression of a MUC1-C(CQC→AQA) mutant, which inhibits MUC1-C homodimerization and function, suppressed both AKT and MEK activation. Moreover, treatment with GO-203, an inhibitor of MUC1-C homodimerization, blocked AKT and MEK signaling and decreased cell survival. The results further demonstrate that targeting MUC1-C suppresses expression of the ZEB1 transcriptional repressor by an AKT-mediated mechanism, and in turn induces miR-200c. In concert with these effects on the ZEB1/miR-200c regulatory loop, targeting MUC1-C was associated with reversal of the epithelial-mesenchymal transition (EMT) and inhibition of self-renewal capacity. Loss of MUC1-C function also attenuated KRAS independence and inhibited growth of KRAS mutant NSCLC cells as tumors in mice. These findings support a model in which targeting MUC1-C inhibits mutant KRAS signaling in NSCLC cells and thereby reverses the EMT phenotype and decreases self-renewal. Impact Journals LLC 2014-08-22 /pmc/articles/PMC4253405/ /pubmed/25245423 Text en Copyright: © 2014 Kharbanda et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited |
spellingShingle | Priority Research Paper Kharbanda, Akriti Rajabi, Hasan Jin, Caining Alam, Maroof Wong, Kwok-Kin Kufe, Donald MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells |
title | MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells |
title_full | MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells |
title_fullStr | MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells |
title_full_unstemmed | MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells |
title_short | MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells |
title_sort | muc1-c confers emt and kras independence in mutant kras lung cancer cells |
topic | Priority Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253405/ https://www.ncbi.nlm.nih.gov/pubmed/25245423 |
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