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Upregulation of Trop-2 quantitatively stimulates human cancer growth

Abstract

Trop-2 is a calcium signal transducer that is associated with transformed cell growth in experimental systems. However, its role in human cancer remains essentially unknown. In this study, we profiled Trop-2 expression in normal human tissues at the mRNA and protein levels. We then systematically compared Trop-2 mRNA and protein levels in tumours with their tissues of origin. We find that Trop-2 expression is invariably upregulated in tumours, regardless of baseline expression in normal tissues, which suggests a corresponding selective advantage. Thus, we investigated the outcome of Trop-2 upregulation on tumour growth. Overexpression of wild-type Trop-2 was shown to be necessary and sufficient to drive cancer growth in a widely invariant manner across cell type and species. Upregulation of Trop-2 was shown to quantitatively stimulate tumour growth, as proportional to expression levels in vivo, and tumour cell growth was abrogated by somatic knockdown of Trop-2 expression. On the other hand, we found no evidence of tumour-associated TROP2 mutations, nor of TROP2 induction of oncogenic transformation per se. Our data support a model where above-baseline expression of wild-type Trop-2 is a key driver of human cancer growth.

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Abbreviations

BRK:

baby rat kidney

CD1-T2 :

CYCLIN D1-TROP2

EST:

expressed sequence tags

HSF1:

heat-shock transcription factor 1

IHC:

immunohistochemistry

mAb:

monoclonal antibody

pAb:

polyclonal antibody

EM:

electron microscopy

MEN-2A:

multiple endocrine neoplasia type 2A

mutRAS :

mutated Harvey RAS

RT:

retro-transcription

SAGE:

serial analysis of gene expression

siRNA:

small inhibitory RNA

wtRAS :

wild-type Harvey RAS.

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Acknowledgements

We are grateful to Professor B Ponder and Dr S Martin for the generous supply of the genomic DNA of MEN-2A, pheochromocytoma and medullary thyroid carcinomas. We thank Dr A Mironov and GV Beznoussenko for help during the course of this work. This research was supported by the Fondazione of the Cassa di Risparmio della Provincia di Chieti, ABO Foundation (CH01D0081), Fondazione compagnia di San Paolo and 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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Trerotola, M., Cantanelli, P., Guerra, E. et al. Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene 32, 222–233 (2013). https://doi.org/10.1038/onc.2012.36

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Keywords

  • Trop-2
  • human tumours
  • cell growth
  • signalling
  • oncogene

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