title: MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells.
abstract: 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.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors.forename: Akriti
authors.initials: A
authors.lastname: Kharbanda
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors.forename: Caining
authors.initials: C
authors.lastname: Jin
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors.forename: Maroof
authors.initials: M
authors.lastname: Alam
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics; D018396:Mucin-1 / Q000096:biosynthesis / Q000235:genetics*; D009368:Neoplasm Transplantation; D010069:Oxadiazoles / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D014157:Transcription Factors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D000071799:Zinc Finger E-box-Binding Homeobox 1; D018631:ras Proteins / Q000235:genetics*
chemical_list: C582521:(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine; C528328:GSK690693; D018398:Homeodomain Proteins; C117307:KRAS protein, human; C533896:MIRN200 microRNA, human; C060192:MUC1 protein, human; D035683:MicroRNAs; D018396:Mucin-1; D010069:Oxadiazoles; D010455:Peptides; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins