Upregulation of RSPO2-GPR48/LGR4 signaling in papillary thyroid carcinoma contributes to tumor progression
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Yea Eun Kang1,*, Jin-Man Kim2,3,*, Koon Soon Kim1,2,*, Joon Young Chang2, Mingyu Jung2, Junguee Lee4, Shinae Yi2, Hyeon Woo Kim2, Jung Tae Kim2, Kyungmin Lee2, Min Jeong Choi2, Seul Ki Kang2, Seong Eun Lee2, Hyon-Seung Yi1, Bon Seok Koo2,5 and Minho Shong1,2
1Department of Endocrinology and Metabolism, College of Medicine, Chungnam National University, Daejeon 35015, South Korea
2Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
3Department of Pathology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
4Department of Pathology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon 34943, Republic of Korea
5Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
*These authors have contributed equally to this work
Minho Shong, email: email@example.com
Keywords: RSPO2; GPR48/LGR4; papillary thyroid carcinoma; BRAFV600E mutation; β-catenin pathway
Received: June 19, 2017 Accepted: October 04, 2017 Published: November 25, 2017
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.
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