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The expression of the truncated isoform of somatostatin receptor subtype 5 associates with aggressiveness in medullary thyroid carcinoma cells

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Abstract

The truncated somatostatin receptor variant sst5TMD4 associates with increased invasiveness and aggressiveness in breast cancer. We previously found that sst5 activation may counteract sst2 selective agonist effects in a medullary thyroid carcinoma (MTC) cell line, the TT cells, and that sst5TMD4 is overexpressed in poorly differentiated thyroid cancers. The purpose of this study is to evaluate sst5TMD4 expression in a series of human MTC and to explore the functional role of sst5TMD4 in TT cells. We evaluated sst5TMD4 and sst5 expression in 36 MTC samples. Moreover, we investigated the role of sst5TMD4 in TT cells evaluating cell number, DNA synthesis, free cytosolic calcium concentration ([Ca2+]i), calcitonin and vascular endothelial growth factor levels, cell morphology, protein expression, and invasion. We found that in MTC the balance between sst5TMD4 and sst5 expression influences disease stage. sst5TMD4 overexpression in TT cells confers a greater growth capacity, blocks sst2 agonist-induced antiproliferative effects, modifies the cell phenotype, decreases E-cadherin and phosphorylated β-catenin levels, increases vimentin, total β-catenin and phosphorylated GSK3B levels (in keeping with the development of epithelial to mesenchymal transition), and confers a greater invasion capacity. This is the first evidence indicating that sst5TMD4 is expressed in human MTC cells, where it associates with more aggressive behavior, suggesting that sst5TMD4 might play a functionally relevant role.

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Acknowledgments

We would like to that Michael D. Culler (Ipsen Biomeasure Inc., Milford, MA, USA) and Novartis Oncology (Italy) for providing the sst selective agonists and SOM230 (Pasireotide), respectively. We would like to thank Renzo Zatelli for the support in the statistical analysis. This work was supported by grants from the Italian Ministry of Education, Research and University (FIRB RBAP11884 M, RBAP1153LS, 2010TYCL9B_002), Fondazione Cassa di Risparmio di Ferrara, and Associazione Italiana per la Ricerca sul Cancro (AIRC) in collaboration with Laboratorio in rete del Tecnopolo “Tecnologie delle terapie avanzate” (LTTA) of the University of Ferrara, and by grants from BIO-139, CTS-1406 (Junta de Andalucía), BFU2013-43282 (MINECO/FEDER), PI13/00651 (Instituto de Salud Carlos III). CIBERObn es una iniciativa del Instituto de Salud Carlos III

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    Authors and Affiliations

    1. Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Via Savonarola 9, 44100, Ferrara, Italy

      Daniela Molè, Erica Gentilin, Teresa Gagliano, Federico Tagliati, Roberta Rossi, Ettore degli Uberti & Maria Chiara Zatelli

    2. Laboratorio in rete del Tecnopolo “Tecnologie delle terapie avanzate” (LTTA), University of Ferrara, Ferrara, Italy

      Erica Gentilin, Ettore degli Uberti & Maria Chiara Zatelli

    3. Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia, and CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, University of Cordoba, 14014, Córdoba, Spain

      Alejandro Ibañez-Costa, Manuel D. Gahete, Raúl M. Luque & Justo P. Castaño

    4. Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Via Giustiniani 2, Padua, Italy

      Maria Rosa Pelizzo

    5. Depatment of Surgery, University of Ferrara, Via Savonarola 9, 44100, Ferrara, Italy

      Giancarlo Pansini

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    1. Daniela Molè
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    2. Erica Gentilin
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    3. Alejandro Ibañez-Costa
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    4. Teresa Gagliano
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    Correspondence to Maria Chiara Zatelli.

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    Daniela Molè and Erica Gentilin have contributed equally to this work.

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    Molè, D., Gentilin, E., Ibañez-Costa, A. et al. The expression of the truncated isoform of somatostatin receptor subtype 5 associates with aggressiveness in medullary thyroid carcinoma cells. Endocrine 50, 442–452 (2015). https://doi.org/10.1007/s12020-015-0594-x

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