Abstract
The signaling pathway involving the R-spondins and its cognate receptor, GPR48/LGR4, is crucial in development and carcinogenesis. However, the functional implications of the R-spondin-GPR48/LGR4 pathway in thyroid remain to be identified. The aim of this study was to investigate the role of R-spondin-GPR48/LGR4 signaling in papillary thyroid carcinomas. We retrospectively reviewed a total of 214 patients who underwent total thyroidectomy and cervical lymph node dissection for papillary thyroid carcinoma. The role of GPR48/LGR4 in proliferation and migration was examined in thyroid cancer cell lines. R-spondin 2, and GPR48/LGR4 were expressed at significantly higher levels in thyroid cancer than in normal controls. Elevated GPR48/LGR4 expression was significantly associated with tumor size (P=0.049), lymph node metastasis (P=0.004), recurrence (P=0.037), and the BRAFV600E mutation (P=0.003). Moreover, high GPR48/LGR4 expression was an independent risk factor for lymph node metastasis (P=0.027) and the BRAFV600E mutation (P=0.009). in vitro assays demonstrated that elevated expression of GPR48/LGR4 promoted proliferation and migration of thyroid cancer cells, whereas downregulation of GPR48/LGR4 decreased proliferation and migration by inhibition of the β-catenin pathway. Moreover, treatment of thyroid cancer cells with exogenous R-spondin 2 induced activation of the β-catenin pathway through GPR48/LGR4. The R-spondin 2-GPR48/LGR4 signaling axis also induced the phosphorylation of ERK, as well as phosphorylation of LRP6 and serine 9 of GSK3β. Our findings demonstrate that upregulation of the R-spondin 2-GPR48/LGR4 pathway contributes to tumor aggressiveness in papillary thyroid carcinoma by promoting ERK phosphorylation, suggesting that this pathway represents a novel therapeutic target for treatment of differentiated thyroid cancer.
Highlights
G-protein coupled receptors (GPCRs), including thyrotropin receptor, are important in both normal thyrocytes and differentiated thyroid cancer cells [1]
Our findings demonstrate that upregulation of the R-spondin 2-G-protein coupled receptor 48 (GPR48)/LGR4 pathway contributes to tumor aggressiveness in papillary thyroid carcinoma by promoting ERK phosphorylation, suggesting that this pathway represents a novel therapeutic target for treatment of differentiated thyroid cancer
Neither inhibitor affected the expression of GPR48/LGR4 mRNA (Supplementary Figure 2). These results suggest that the MAPK/extracellular signal– regulated kinases (ERK1/2) pathway is required for GPR48/LGR48mediated β-catenin signaling, and that post-transcriptional regulation of GPR48/LGR4 in differentiated thyroid carcinoma may be influenced by inhibition of RAF and MEK
Summary
G-protein coupled receptors (GPCRs), including thyrotropin receptor, are important in both normal thyrocytes and differentiated thyroid cancer cells [1]. The Wnt/β-catenin is essential in embryonic development as well as in self-renewal and maintenance of adult stem cells. Their biological effects are mediated by high-affinity binding to LGR receptors and sequential induction of LRP6 phosphorylation [8,9,10,11]. Lack of RSPO2 signaling in the embryonic stage results in thyroid malformation [12, 13] These findings showed that the RSPO signaling axis is indispensable for normal development of the thyroid gland in animal models, but the expression status and roles of RSPO–GPR48/LGR4 signaling components in human thyroid gland remain to be elucidated
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
