The GIP/GIPR axis in medullary thyroid cancer: clinical and molecular findings
Open accessAbstract
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 Ca 2+ , 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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Higher expression of GIP receptor was found in tumor rather than normal tissue in rats and human specimens of medullary thyroid cancer.
“However, a higher expression of GIP receptor was found in tumor rather than normal tissue in rats and human specimens of medullary thyroid cancer”
From The real-world safety profile of tirzepatide: pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database (2024) · cites this paper as [31]
Stimulation of GIP receptor resulted in increased secretion of calcitonin.
“and the stimulation of GIP receptor resulted in increased secretion of calcitonin [31].”
From The real-world safety profile of tirzepatide: pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database (2024) · cites this paper as [31]
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Cites
Yaşlı Kadınlarda Üreme Sağlığı
Kokanalı, D., & Engin Üstün, Y. (n.d.) · DergiPark (Istanbul University) · Cited by 170,090 · see citing works
Biology of Incretins: GLP-1 and GIP
Baggio, L. L., & Drucker, D. J. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.03.054 · Cited by 3,639 · see citing works
(2013) · Gastroenterology Research · doi:10.1053/j · Cited by 2,759 · see citing works
Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma
Wells, S. A., Asa, S. L., Dralle, H., Elisei, R., Evans, D. B., Gagel, R. F., Lee, N. Y., Machens, A., Moley, J. F., Pacini, F., et al. (2015) · Thyroid · doi:10.1089/thy.2014.0335 · Cited by 2,444 · see citing works
STIMULATION OF INSULIN SECRETION BY GASTRIC INHIBITORY POLYPEPTIDE IN MAN. <sup>1</sup>
Dupre, J., Ross, S. A., Watson, D., & Brown, J. C. (1973) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-37-5-826 · Cited by 860 · see citing works
GIP and GLP-1, the two incretin hormones: Similarities and differences
Seino, Y., Fukushima, M., & Yabe, D. (2010) · Journal of Diabetes Investigation · doi:10.1111/j.2040-1124.2010.00022.x · Cited by 746 · see citing works
Trümper, A., Trümper, K., & Hörsch, D. (2002) · Journal of Endocrinology · doi:10.1677/joe.0.1740233 · Cited by 193 · see citing works
Yabe, D., & Seino, Y. (2011) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2011.07.010 · Cited by 189 · see citing works
Romei, C., Cosci, B., Renzini, G., Bottici, V., Molinaro, E., Agate, L., Passannanti, P., Viola, D., Biagini, A., Basolo, F., et al. (2010) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2010.03900.x · Cited by 127 · see citing works
Elisei, R., Tacito, A., Ramone, T., Ciampi, R., Bottici, V., Cappagli, V., Viola, D., Matrone, A., Lorusso, L., Valerio, L., et al. (2019) · Genes · doi:10.3390/genes10090698 · Cited by 101 · see citing works
Widenmaier, S. B., Ao, Z., Kim, S., Warnock, G. L., & McIntosh, C. H. S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.060178 · Cited by 96 · see citing works
deBustros, A., Baylin, S. B., Levine, M. A., & Nelkin, B. D. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)57508-1 · Cited by 92 · see citing works
Lin, D. T., Hassan, M. C., Pazaitou‐Panayiotou, K., Ruan, D. T., Gawande, A. A., Gaz, R. D., Moore, F. D., Hodin, R. A., Stephen, A. E., Sadow, P. M., et al. (2011) · Surgery · doi:10.1016/j.surg.2011.09.043 · Cited by 82 · see citing works
Waser, B., Beetschen, K., Pellegata, N. S., & Reubi, J. C. (2011) · Neuroendocrinology · doi:10.1159/000330447 · Cited by 80 · see citing works
SZECOWKA, J., Grill, V., Sandberg, E., & Efendić, S. (1982) · European Journal of Endocrinology · doi:10.1530/acta.0.0990416 · Cited by 63 · see citing works
Aberrant G-protein coupled hormone receptor in adrenal diseases
St‐Jean, M., Ghorayeb, N. E., Bourdeau, I., & Lacroix, A. (2018) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2018.01.003 · Cited by 58 · see citing works
Wu, T., Rayner, C. K., & Horowitz, M. (2015) · Handbook of experimental pharmacology · doi:10.1007/164_2015_9 · Cited by 58 · see citing works
Waser, B., Rehmann, R., Sanchez, C., Fourmy, D., & Reubi, J. C. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-2454 · Cited by 53 · see citing works
Occhi, G., Losa, M., Albiger, N. M. E., Trivellin, G., Regazzo, D., Scanarini, M., Garcia, J. L. M., Fröhlich, B., Ferasin, S., Terreni, M. R., et al. (2011) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2011.02155.x · Cited by 50 · see citing works
Self-citationRegazzo, D., Losa, M., Albiger, N. M., Terreni, M. R., Vazza, G., Ceccato, F., Emanuelli, E., Denaro, L., Scaroni, C. M., & Occhi, G. (2017) · European Journal of Endocrinology · doi:10.1530/eje-16-0831 · Cited by 50 · see citing works
Self-citationKubota, A., Yamada, Y., Yasuda, K., Someya, Y., Ihara, Y., Kagimoto, S., Watanabe, R., Kuroe, A., Ishida, H., & Seino, Y. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6743 · Cited by 49 · see citing works
Pan, D., Wen, D., Luo, Y., Chen, G., Yang, H., Chen, J., & He, Y. (2017) · OncoTargets and Therapy · doi:10.2147/ott.s135593 · Cited by 48 · see citing works
Park, H., Park, J. T., Choi, M. S., Kim, J., Kim, H., Shin, J. H., Kim, J., Kim, J. S., Kim, S. W., Chung, J. H., et al. (2020) · Cancers · doi:10.3390/cancers12102894 · Cited by 48 · see citing works
Phosphatases control PKA-dependent functional microdomains at the outer mitochondrial membrane
Burdyga, A., Surdo, N. C., Monterisi, S., Benedetto, G. D., Grisan, F., Penna, E., Pellegrini, L., Zaccolo, M., Bortolozzi, M., Swietach, P., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1806318115 · Cited by 46 · see citing works
Self-citationBates, H. E., Campbell, J. E., Ussher, J. R., Baggio, L. L., Maida, A., Seino, Y., & Drucker, D. J. (2011) · Diabetes · doi:10.2337/db11-1060 · Cited by 43 · see citing works
Aberrant GPCR expression is a sufficient genetic event to trigger adrenocortical tumorigenesis
Mazzuco, T. L., Chabre, O., Feige, J., & Thomas, M. (2006) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2006.12.034 · Cited by 41 · see citing works
Gallwitz, B., Witt, M., Morys‐Wortmann, C., Fölsch, U. R., & Schmidt, W. E. (1996) · Regulatory Peptides · doi:10.1016/0167-0115(96)00019-5 · Cited by 41 · see citing works
Scaroni, C. M., Albiger, N. M. E., Daniele, A., Dassie, F., Romualdi, C., Vazza, G., Regazzo, D., Ferraù, F., Barresi, V., Maffeis, V., et al. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-01360 · Cited by 38 · see citing works
Self-citationRegazzo, D., Barbot, M., Scaroni, C. M., Albiger, N. M. E., & Occhi, G. (2020) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-019-09536-6 · Cited by 31 · see citing works
Self-citationGlucose-dependent insulinotropic polypeptide stimulates the proliferation of colorectal cancer cells
Prabakaran, D., Wang, B., Feuerstein, J. D., Sinclair, J. A., Bijpuria, P., Jepeal, L. I., & Wolfe, M. M. (2010) · Regulatory Peptides · doi:10.1016/j.regpep.2010.04.005 · Cited by 29 · see citing works
Körner, M., Waser, B., & Reubi, J. C. (2015) · Neuroendocrinology · doi:10.1159/000371804 · Cited by 26 · see citing works
Bertazza, L., Sensi, F., Cavedon, E., Watutantrige‐Fernando, S., Censi, S., Manso, J., Vianello, F., Ide, E. C., Iacobone, M., Pezzani, R., et al. (2018) · Endocrinology · doi:10.1210/en.2018-00124 · Cited by 25 · see citing works
Self-citationGIPR expression in gastric and duodenal neuroendocrine tumors
Sherman, S. K., Maxwell, J. E., Carr, J. C., Wang, D., O'Dorisio, M. S., O’Dorisio, T. M., & Howe, J. R. (2014) · Journal of Surgical Research · doi:10.1016/j.jss.2014.01.044 · Cited by 22 · see citing works
WESTENDORF, J. M., & Schönbrunn, A. (1985) · Endocrinology · doi:10.1210/endo-116-6-2528 · Cited by 22 · see citing works
Ca2+-Dependent Regulation of Calcitonin Gene Expression by the Transcriptional Repressor DREAM
Matsuda, M., Yamamoto, T.-A., & Hirata, M. (2006) · Endocrinology · doi:10.1210/en.2006-0254 · Cited by 21 · see citing works
Oczko‐Wojciechowska, M., Świerniak, M., Krajewska, J., Kowalska, M., Kowal, M., Stokowy, T., Wojtaś, B., Rusinek, D., Pawlaczek, A., Czarniecka, A., et al. (2017) · Scientific Reports · doi:10.1038/srep42074 · Cited by 21 · see citing works
Targeting glucose-dependent insulinotropic polypeptide receptor for neurodegenerative disorders
Verma, M. K., Goel, R. N., Nandakumar, K., & Nemmani, K. V. S. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2018.1487952 · Cited by 21 · see citing works
Clinical Characteristics of Acromegalic Patients With Paradoxical GH Response to Oral Glucose Load
Mukai, K., Otsuki, M., Tamada, D., Kitamura, T., Hayashi, R., Saiki, A., Goto, Y., Arita, H., Oshino, S., Morii, E., et al. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-00975 · Cited by 18 · see citing works
Regulation of Calcitonin Secretion in Vitro
Raue, F., Zink, A., & Scherübl, H. (1993) · Hormone and Metabolic Research · doi:10.1055/s-2007-1002152 · Cited by 11 · see citing works
Procalcitonin as a marker of medullary thyroid carcinoma
Cancela-Nieto, M. G., Sobrino, P. S., & Velo-García, A. (2020) · Minerva Endocrinology · doi:10.23736/s0391-1977.20.03229-0 · Cited by 5 · see citing works
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Research works printed but not linked: 1
- Reubi JC, Fourmy D, Cordomi A, Tikhonova IG & Gigoux V 2020 GIP receptor: expression in neuroendocrine tumours, internalization, signalling from endosomes and structure-function relationship studies. Peptides 125 170229. (https://doi.org/10.1016/j. peptides.2019.170229) · DOI
Cited by
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Caruso, I., Di Gioia, L., Di Molfetta, S., Caporusso, M., Cignarelli, A., Sorice, G. P., Laviola, L., & Giorgino, F. (2024) · Journal of Endocrinological Investigation · doi:10.1007/s40618-024-02441-z · Cited by 49 · see citing works
Zeng, Y., Luo, Y., Zhao, K., Liu, S., Wu, K., Wu, Y., Du, K., Pan, W., Dai, Y., Liu, Y., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-3703 · Cited by 39 · see citing works
Tirzepatide—Friend or Foe in Diabetic Cancer Patients?
Samuel, S. M., Varghese, E., Kubatka, P., & Büsselberg, D. (2022) · Biomolecules · doi:10.3390/biom12111580 · Cited by 22 · see citing works
“However, in rodents and humans, the expression of GLP-1R and GIPR was significantly higher in MTCs compared to normal thyroid tissue across the same species [82,84].”
BackgroundAberrant hormone receptors regulate a wide spectrum of endocrine tumors
Lacroix, A., Bourdeau, I., Chasseloup, F., Kamenický, P., Lopez, A.-G., Louiset, E., & Lefèbvre, H. (2024) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(24)00200-6 · Cited by 17 · see citing works
Lacroix, A. (2023) · European Journal of Endocrinology · doi:10.1093/ejendo/lvad026 · Cited by 15 · see citing works
Incretin-Based Therapies and Cancer: What’s New?
Medenica, S., Bogdanović, J. M., Vekić, J., Vojinović, T., Babić, I., Bogdanovic, L. M., Maggio, V., El‐Tanani, M., & Rizzo, M. (2025) · Medicina · doi:10.3390/medicina61040678 · Cited by 13 · see citing works
“In a study by Regazzo et al., GIP-R expression in MTC specimens was correlated with tumor progression markers, including larger tumor size, advanced stage, and higher Ki-67 levels, indicating its role as an index of malignancy [66].”
KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas
Chasseloup, F., Regazzo, D., Tosca, L., Proust, A., Kuhn, E., Hage, M. P., Jublanc, C., Mokhtari, K., Nogare, M. D., Avallone, S., et al. (2024) · European Journal of Endocrinology · doi:10.1093/ejendo/lvae013 · Cited by 11 · see citing works
Self-citationGenetically proxied impaired GIPR signaling and risk of 6 cancers
Rogers, M., Gill, D., Ahlqvist, E., Robinson, T., Mariosa, D., Johansson, M., Penha, R. C. C., Dossus, L., Gunter, M. J., Moreno, V. R., et al. (2023) · iScience · doi:10.1016/j.isci.2023.106848 · Cited by 10 · see citing works
“While preclinical studies suggest that GIP can induce cAMP elevation in medullary thyroid cancer cells and proliferation in colorectal cancer cells, no known in vitro or in vivo studies have examined the role of GIP signaling in breast cancer to date.(14,35)”
BackgroundA novel somatostatin receptor ligand for human ACTH – and GH –secreting pituitary adenomas
Regazzo, D., Avallone, S., MacSweeney, C. P., Sergeev, E., Howe, D. C., Godwood, A., Bennett, K. A., Brown, A., Barnes, M., Occhi, G., et al. (2023) · European Journal of Endocrinology · doi:10.1093/ejendo/lvad171 · Cited by 9 · see citing works
Self-citationWeng, D., He, L., Chen, X., Lin, H., Ji, D., Lu, S., Ao, L., & Wang, S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1055412 · Cited by 8 · see citing works
“cAMP signaling triggers the synthesis and secretion of calcitonin, a well-known marker secreted by the parafollicular cells in MTC (36).”
BackgroundTseng, P., Zeng, B., Hsu, C.-W., Sun, C., Suen, M., Carvalho, A. F., Stubbs, B., Chen, Y., Chen, T., Lei, W., et al. (2025) · Journal of Hematology & Oncology · doi:10.1186/s13045-025-01750-x · Cited by 8 · see citing works
“…got more beneficial effect than that specified in the row in genetically predisposed populations, such as those with a family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, tirzepatide might further elevate thyroid cancer risk through GIP-mediated pathways [148].”
Paradoxical GH increase after oral glucose load in subjects with and without acromegaly
Ceccato, F., Vedolin, C. K., Voltan, G., Antonelli, G., Barbot, M., Basso, D., Regazzo, D., Scaroni, C. M., & Occhi, G. (2023) · Journal of Endocrinological Investigation · doi:10.1007/s40618-023-02138-9 · Cited by 6 · see citing works
“Recently, we have confirmed that the aberrant expression of GIPR is an early event in the neo-plastic transformation in medullary thyroid cancer [22, 23], which present a high tumor-to-normal tissue ratio (T/N ratio) for GIPR, like most neuroendocrine tumours [23].”
BackgroundSelf-citationNogare, M. D., D’Annunzio, S., Vazza, G., Regazzo, D., Picello, L., Denaro, L., Voltan, G., Scaroni, C. M., Ceccato, F., & Occhi, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119264 · Cited by 5 · see citing works
“Working concentrations of 5-Aza-dC were established by testing its effects on the viability of GH3 cells, in 96-well plates, using the MTT proliferation assay (Merck, Milan, Italy), as described elsewhere [8].”
BackgroundMethodInfluentialSelf-citationNeumann, J., Hofmann, B., & Gergs, U. (2025) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-025-04485-1 · Cited by 3 · see citing works
Incretin Mimetics in Cancer and Cardiovascular Disease
Leong, D. P., Gong, S., Sattar, N. A., Narayan, V., Reizine, N. M., Gerstein, H. C., & Vellky, J. E. (2026) · JACC CardioOncology · doi:10.1016/j.jaccao.2025.12.003 · Cited by 3 · see citing works
Haase, A., Alefeld, E., Yalinci, F., Meenen, D. V., Busch, M. A., & Dünker, N. (2024) · Cancers · doi:10.3390/cancers16091656 · Cited by 2 · see citing works
“Informed consent was obtained from all the subjects involved in this study.”
MethodChasseloup, F. (2022) · theses.fr (ABES) · doi:10.70675/ddec5b6dzf376z4aadz9970zf0bf052c6f02
- Authors
- Regazzo, D., Bertazza, L., Galletta, E., Barollo, S., Mondin, A., Zovato, S., Iacobone, M., Zilio, E., Scaroni, C., Radu, C. M., di Benedetto, G., Mian, C., Lefkimmiatis, K., & Occhi, G.
- Affiliations
- University of Padua (IT)
- Istituto Oncologico Veneto (IT)
- 6Neuroscience Institute, National Research Council, Padova Section, Padova, Italy
- University of Pavia (IT)
- Venue
- Endocrine-Related Cancer
- Publisher
- Bioscientifica
- Published
- 2022-05-01
- Volume
- 29
- Issue
- 5
- Pages
- 273-284
- ISSN
- 1351-0088 (ISSN-L)
- 1479-6821
- OpenAlex
- W4220768125
- Cited by
- 17
- References
- 37
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 2
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrine Related Cancer (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Keywords
- medullary thyroid carcinoma, glucose-dependent insulinotropic polypeptide receptor, calcitonin secretion, tumor-to-normal tissue ratio, Ki-67, cAMP signaling, calcium signaling, PI3K/Akt signaling, MAPK/ERK1/2 pathway, prognostic factors, diagnostic biomarkers, tumor progression
- MeSH terms
- Calcitonin, Gastric Inhibitory Polypeptide, Humans, Receptors, Gastrointestinal Hormone, Thyroid Neoplasms, Carcinoma, Neuroendocrine, Phosphatidylinositol 3-Kinases
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