title: DNp73 exerts function in metastasis initiation by disconnecting the inhibitory role of EPLIN on IGF1R-AKT/STAT3 signaling.
abstract: Dissemination of cancer cells from primary tumors is the key event in metastasis, but specific determinants are widely unknown. Here, we show that DNp73, an inhibitor of the p53 tumor suppressor family, drives migration and invasion of nonmetastatic melanoma cells. Knockdown of endogenous DNp73 reduces this behavior in highly metastatic cell lines. Tumor xenografts expressing DNp73 show a higher ability to invade and metastasize, while growth remains unaffected. DNp73 facilitates an EMT-like phenotype with loss of E-cadherin and Slug upregulation. We provide mechanistic insight toward regulation of LIMA1/EPLIN by p73/DNp73 and demonstrate a direct link between the DNp73-EPLIN axis and IGF1R-AKT/STAT3 activation. These findings establish initiation of the invasion-metastasis cascade via EPLIN-dependent IGF1R regulation as major activity of DNp73.
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Schillingallee 69, 18057 Rostock, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Steder
authors.forename: Vijay
authors.initials: V
authors.lastname: Alla
authors.forename: Claudia
authors.initials: C
authors.lastname: Meier
authors.forename: Alf
authors.initials: A
authors.lastname: Spitschak
authors.forename: Jens
authors.initials: J
authors.lastname: Pahnke
authors.forename: Katharina
authors.initials: K
authors.lastname: Fürst
authors.forename: Bhavani S
authors.initials: BS
authors.lastname: Kowtharapu
authors.forename: David
authors.initials: D
authors.lastname: Engelmann
authors.forename: Janine
authors.initials: J
authors.lastname: Petigk
authors.forename: Friederike
authors.initials: F
authors.lastname: Egberts
authors.forename: Susanne G
authors.initials: SG
authors.lastname: Schäd-Trcka
authors.forename: Gerd
authors.initials: G
authors.lastname: Gross
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Nettelbeck
authors.forename: Annett
authors.initials: A
authors.lastname: Niemetz
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Pützer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D003598:Cytoskeletal Proteins; C485741:D15Ertd366e protein, mouse; D004268:DNA-Binding Proteins; C403263:LIMA1 protein, human; D009687:Nuclear Proteins; D050796:STAT3 Transcription Factor; C495901:TP53 protein, human; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt