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Endocr Relat Cancer. 2019 Jan 1;26(1):197-214. doi: 10.1530/ERC-18-0310.

DDR1 regulates thyroid cancer cell differentiation via IGF-2/IR-A autocrine signaling loop.

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School of Human and Social Sciences, 'Kore' University of Enna, Enna, Italy.
Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.
Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
Center of Experimental Oncology and Hematology, AOU Policlinico Vittorio Emanuele, Catania, Italy.
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
Unit of Thyroid and Neck Surgery, Policlinico Vittorio Emanuele, University of Catania, Catania, Italy.
Unit of Pathology, Policlinico Vittorio Emanuele, University of Catania, Catania, Italy.
Department of Urology and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.


Patients with thyroid cancers refractory to radioiodine (RAI) treatment show a limited response to various therapeutic options and a low survival rate. The recent use of multikinase inhibitors has also met limited success. An alternative approach relies on drugs that induce cell differentiation, as the ensuing increased expression of the cotransporter for sodium and iodine (NIS) may partially restore sensitivity to radioiodine. The inhibition of the ERK1/2 pathway has shown some efficacy in this context. Aggressive thyroid tumors overexpress the isoform-A of the insulin receptor (IR-A) and its ligand IGF-2; this IGF-2/IR-A loop is associated with de-differentiation and stem-like phenotype, resembling RAI-refractory tumors. Importantly, IR-A has been shown to be positively modulated by the non-integrin collagen receptor DDR1 in human breast cancer. Using undifferentiated human thyroid cancer cells, we now evaluated the effects of DDR1 on IGF-2/IR-A loop and on markers of cell differentiation and stemness. DDR1 silencing or downregulation caused significant reduction of IR-A and IGF-2 expression, and concomitant increased levels of differentiation markers (NIS, Tg, TSH, TPO). Conversely, markers of epithelial-to-mesenchymal transition (Vimentin, Snail-2, Zeb1, Zeb2 and N-Cadherin) and stemness (OCT-4, SOX-2, ABCG2 and Nanog) decreased. These effects were collagen independent. In contrast, overexpression of either DDR1 or its kinase-inactive variant K618A DDR1-induced changes suggestive of less differentiated and stem-like phenotype. Collagen stimulation was uneffective. In conclusion, in poorly differentiated thyroid cancer, DDR1 silencing or downregulation blocks the IGF-2/IR-A autocrine loop and induces cellular differentiation. These results may open novel therapeutic approaches for thyroid cancer.


Discoidin Domain Receptor 1; insulin receptor isoform-A; insulin-like growth factor-2; thyroid cancer


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