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DDR1 regulates thyroid cancer cell differentiation via IGF-2/IR-A autocrine signaling loop
- Source :
- Endocrine-related cancer. 26(1)
- Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Cancer Research
Endocrinology, Diabetes and Metabolism
Cellular differentiation
Thyroid Gland
Biology
Thyroid cancer
Collagen receptor
03 medical and health sciences
0302 clinical medicine
Endocrinology
Downregulation and upregulation
Discoidin Domain Receptor 1
Antigens, CD
Insulin-Like Growth Factor II
Cell Line, Tumor
medicine
Humans
Thyroid Neoplasms
insulin receptor
RNA, Small Interfering
Autocrine signalling
Thyroid
Cancer
Cell Differentiation
medicine.disease
Receptor, Insulin
IGF-2
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Cancer cell
Cancer research
Thyroid cancer, insulin receptor, IGF-2
Subjects
Details
- ISSN :
- 14796821
- Volume :
- 26
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Endocrine-related cancer
- Accession number :
- edsair.doi.dedup.....5b788667773e8418f22ac02ddf10aa91