title: p73 and IGF1R Regulate Emergence of Aggressive Cancer Stem-like Features via miR-885-5p Control.
abstract: Cancer stem-like cells (CSC) have been proposed to promote cancer progression by initiating tumor growth at distant sites, suggesting that stem-like cell features can support metastatic efficiency. Here, we demonstrate that oncogenic DNp73, a dominant-negative variant of the tumor-suppressor p73, confers cancer cells with enhanced stem-like properties. DNp73 overexpression in noninvasive melanoma and lung cancer cells increased anchorage-independent growth and elevated the expression of the pluripotency factors CD133, Nanog, and Oct4. Conversely, DNp73 depletion in metastatic cells downregulated stemness genes, attenuated sphere formation and reduced the tumor-initiating capability of spheroids in tumor xenograft models. Mechanistic investigations indicated that DNp73 acted by attenuating expression of miR-885-5p, a direct regulator of the IGF1 receptor (IGF1R) responsible for stemness marker expression. Modulating this pathway was sufficient to enhance chemosensitivity, overcoming DNp73-mediated drug resistance. Clinically, we established a correlation between low p73 function and high IGF1R/CD133/Nanog/Oct4 levels in melanoma specimens that associated with reduced patient survival. Our work shows how DNp73 promotes cancer stem-like features and provides a mechanistic rationale to target the DNp73-IGF1R cascade as a therapeutic strategy to eradicate CSC.
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Meier
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Hardtstock
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Joost
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
authors.forename: Vijay
authors.initials: V
authors.lastname: Alla
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany. brigitte.puetzer@med.uni-rostock.de.
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Pützer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism; D014162:Transfection; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C000597236:IGF1R protein, human; C574934:MIRN885 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D017451:Receptors, Somatomedin; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D017526:Receptor, IGF Type 1