The GIP/GIPR axis in medullary thyroid cancer: clinical and molecular findings

in Endocrine-Related Cancer
Authors:
Daniela Regazzo Department of Medicine – Endocrinology Unit, Padova University Hospital, Padova, Italy

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Loris Bertazza Department of Medicine – Endocrinology Unit, Padova University Hospital, Padova, Italy

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Eva Galletta Department of Biology, University of Padova, Padova, Italy

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Susi Barollo Department of Medicine – Endocrinology Unit, Padova University Hospital, Padova, Italy

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Alberto Mondin Department of Medicine – Endocrinology Unit, Padova University Hospital, Padova, Italy

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Stefania Zovato Hereditary Tumors Unit, Veneto Institute of Oncology-IOV-IRCCS, Padova, Italy

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Maurizio Iacobone Department of Surgery, Oncology and Gastroenterology – Endocrine Surgery Unit, Padova University Hospital, Padova, Italy

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Eleonora Zilio Department of Biology, University of Padova, Padova, Italy

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Carla Scaroni Department of Medicine – Endocrinology Unit, Padova University Hospital, Padova, Italy

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Claudia Maria Radu Department of Medicine – General Medicine and Thrombotic and Haemorrhagic Diseases Unit, Padova University Hospital, Padova, Italy

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https://orcid.org/0000-0002-5548-9785
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Giulietta di Benedetto Neuroscience Institute, National Research Council, Padova Section, Padova, Italy
Foundation for Advanced Biomedical Research, Veneto Institute of Molecular Medicine (VIMM), Padova, Italy

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Caterina Mian Department of Medicine – Endocrinology Unit, Padova University Hospital, Padova, Italy

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Konstantinos Lefkimmiatis Foundation for Advanced Biomedical Research, Veneto Institute of Molecular Medicine (VIMM), Padova, Italy
Department of Molecular Medicine, University of Pavia, Pavia, Italy

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Gianluca Occhi Department of Biology, University of Padova, Padova, Italy

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https://orcid.org/0000-0003-4065-4677

Correspondence should be addressed to G Occhi: gianluca.occhi@unipd.it
DOI:
https://doi.org/10.1530/ERC-21-0258
Volume/Issue:
Volume 29: Issue 5
Article Type:
Research Article
Page Range:
273–284
Online Publication Date:
29 Apr 2022
Copyright:
© Society for Endocrinology 2022
Restricted access
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The improper expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) and the GIP/GIPR axis activation has been increasingly recognized in endocrine tumors, with a potential diagnostic and prognostic value. A high tumor-to-normal tissue ratio (T/N ratio) of GIPR was reported both in humans’ and in rats’ medullary thyroid cancer (MTC), suggesting a direct link between the neoplastic transformation and the mechanism of receptor overexpression. In this study, we evaluated the potential diagnostic and prognostic significance of GIPR expression in a large cohort of MTC patients by correlating GIPR mRNA steady-state levels to clinical phenotypes. The molecular effect of GIP/GIPR axis stimulation in MTC-derived cells was also determined. We detected GIPR expression in ~80% of tumor specimens, especially in sporadic, larger, advanced-stage cancers with higher Ki-67 values. GIPR stimulation induced cAMP elevation in MTC-derived cells and a small but significant fluctuation in Ca2+, both likely associated with increased calcitonin secretion. On the contrary, the effects on PI3K-Akt and MAPK-ERK1/2 signaling pathways were marginal. To conclude, our data confirm the high T/N GIPR ratio in MTC tumors and suggest that it may represent an index for the degree of advancement of the malignant process. We have also observed a functional coupling between GIP/GIPR axis and calcitonin secretion in MTC models. However, the molecular mechanisms underlying this process and the possible implication of GIP/GIPR axis activation in MTC diagnosis and prognosis need further evaluation.

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© Society for Endocrinology 2022
Page(s):
12
Received Date:
10 Mar 2022
Accepted Date:
15 Mar 2022
Print Publication Date:
01 May 2022
Online Publication Date:
29 Apr 2022
Keywords:
medullary thyroid cancer; GIP/GIPR axis; neuroendocrine tumors; cell signaling; thyroid

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