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The Trop-2 signalling network in cancer growth

Oncogene volume 32, pages 1594–1600 (2013)Cite this article

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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.

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Abbreviations

AIRE:

autoimmune regulator

CREB:

cyclic AMP-responsive-element binding protein

FOXM1:

forkhead box M1

Get:

Grainyhead-like epithelial transactivator

IPA:

Ingenuity pathways analysis

TCF:

T-cell factor

WTAP:

Wilms’ tumour-associated protein

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Acknowledgements

This study was supported by the Fondazione of the Cassa di Risparmio della Provincia di Chieti, ABO Foundation (Grant CH01D0081), Fondazione compagnia di San Paolo, and the Italian Ministry of Health (RicOncol RF-EMR-2006-361866). MT was a recipient of a scholarship from the Italian Foundation for Cancer Research (FIRC, Italy).

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Author notes

  1. M Trerotola

    Present address: 3Current address: Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA, USA.,

Authors and Affiliations

  1. Department of Oncology and Experimental Medicine and CeSI, Unit of Cancer Pathology, Foundation University ‘G. d’Annunzio’, Chieti, Italy

    E Guerra, M Trerotola, A L Aloisi, R Tripaldi, G Vacca, R La Sorda, R Lattanzio, M Piantelli & S Alberti

  2. Department of Neuroscience and Imaging, University ‘G. d’Annunzio’, Chieti, Italy

    S Alberti

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Correspondence to S Alberti.

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Supplementary Table 1a & 1b accompanies the paper on the Oncogene website

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Guerra, E., Trerotola, M., Aloisi, A. et al. The Trop-2 signalling network in cancer growth. Oncogene 32, 1594–1600 (2013). https://doi.org/10.1038/onc.2012.151

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