title: The Trop-2 signalling network in cancer growth.
abstract: Our findings show that upregulation of a wild-type Trop-2 has a key controlling role in human cancer growth, and that tumour development is quantitatively driven by Trop-2 expression levels. However, little is known about the regulation of expression of the TROP2 gene. Hence, we investigated the TROP2 transcription control network. TROP2 expression was shown to depend on a highly interconnected web of transcription factors: TP63/TP53L, ERG, GRHL1/Get-1 (grainyhead-like epithelial transactivator), HNF1A/TCF-1 (T-cell factor), SPI1/PU.1, WT (Wilms' tumour)1, GLIS2, AIRE (autoimmune regulator), FOXM1 (forkhead box M1) and FOXP3, with HNF4A as the major network hub. TROP2 upregulation was shown to subsequently drive the expression and activation of CREB1 (cyclic AMP-responsive-element binding protein), Jun, NF-κB, Rb, STAT1 and STAT3 through induction of the cyclin D1 and ERK (extracellular signal regulated kinase)/MEK (MAPK/ERK kinase) pathways. Growth-stimulatory signalling through NF-κB, cyclin D1 and ERK was shown to require an intact Trop-2 cytoplasmic tail. Network hubs and interacting partners are co-expressed with Trop-2 in primary human tumours, supporting a role of this signalling network in cancer growth.
authors.affiliation: Unit of Cancer Pathology, Department of Oncology and Experimental Medicine and CeSI, Foundation University 'G. d'Annunzio', Chieti, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Guerra
authors.forename: M
authors.initials: M
authors.lastname: Trerotola
authors.forename: A L
authors.initials: AL
authors.lastname: Aloisi
authors.forename: R
authors.initials: R
authors.lastname: Tripaldi
authors.forename: G
authors.initials: G
authors.lastname: Vacca
authors.forename: R
authors.initials: R
authors.lastname: La Sorda
authors.forename: R
authors.initials: R
authors.lastname: Lattanzio
authors.forename: M
authors.initials: M
authors.lastname: Piantelli
authors.forename: S
authors.initials: S
authors.lastname: Alberti
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D019938:Cyclin D1 / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000951:Antigens, Neoplasm; C081876:CKAP4 protein, human; D015815:Cell Adhesion Molecules; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D016328:NF-kappa B; C499380:TACSTD2 protein, human; D019938:Cyclin D1; D048049:Extracellular Signal-Regulated MAP Kinases