RESUMEN
Normal thyroid tissue displays a prevalent expression of ERß than ERα, which drastically turns upside down in the initiation and progression of papillary thyroid cancer (PTC). The underlying molecular mechanism of this phenomenon remains unclear. Here, we demonstrated that ERα and ERß were coexpressed in human thyroid tissues and cells. ERα mRNA (A-1) and ERß mRNA (0N-1), transcribed from Promoter A of ERα gene and Promoter 0N of ERß gene, respectively, were the major mRNA isoforms which mainly contributed to total ERα mRNA and total ERß mRNA in human thyroid-derived cell lines and tissues. The expression levels of ERα mRNA (A-1) and total ERα mRNA were gradually increased, and those of ERß mRNA (0N-1) and total ERß mRNA were decreased by degree in the initiation and progression of PTC. No aberrant DNA methylation of ERα 5'-untranslated region was involved in its up-regulation; however, aberrant DNA methylation in Promoter 0N and Exon 0N of ERß gene was found to be involved in its down-regulation in the initiation and progression of PTC. ERß can repress ERα gene transcription via recruitment of NCoR and displacement of RNA polymerase II at the Sp1 site in ERα Promoter A-specific region in thyroid-derived cells. It is suggested that DNA methylation of CpG islands in Promoter 0N and Exon 0N of ERß gene leads to a decreased ERß gene expression, which attenuates its inhibitory effect on ERα gene transcription and results in an increased ERα gene expression, cell proliferation, initiation, and progression of PTC.
Asunto(s)
Receptor alfa de Estrógeno/genética , Regulación Neoplásica de la Expresión Génica/genética , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/genética , Línea Celular Tumoral , Regulación hacia Abajo , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Humanos , Receptores de Estrógenos/metabolismo , Regulación hacia ArribaRESUMEN
OBJECTIVE: To investigate the effects of ubiquitin-like PDH and ring finger domain 1 (UHRF1) on the expression ratio of estrogen receptor (ER) α/ERß, and to explore the experimental mechanism of UHRF1 affecting the proliferation, invasion and migration of BCPAP cells in papillary thyroid carcinoma. METHODS: The protein and mRNA expressions of UHRF1, ERα and ERß in normal thyroid Nthy-ori3-1 cells and thyroid papillary carcinoma BCPAP cells were detected by Western blot and qRT-PCR. BCPAP cells were treated with Scrambled siRNA and UHRF1 siRNA, respectively. The expressions of ER α and ER ß mRNAs were detected by qRT-PCR. MTT and Transwell were used to determine the proliferation, invasion and migration in each group of BCPAP cells. RESULTS: Compared with Nthy-ori3-1 cells, the expressions of UHRF1 and ERα proteins and mRNAs in BCPAP cells were significantly up-regulated ( P<0.05), while the expressions of ERß protein and mRNA were significantly down-regulated ( P<0.05). Compared with the control group and Scrambled siRNA group, the expression of ER α mRNA in BCPAP cells transfected with UHRF1 siRNA was significantly decreased ( P<0.05), while the expression of ER ß mRNA was significantly increased ( P<0.05). The proliferation, invasion and migration of BCPAP cells transfected with UHRF1 siRNA were significantly decreased ( P<0.05). CONCLUSION: UHRF1 upregulates ERα/ERß expression ratio and promotes proliferation, invasion and migration of BCPAP cells in papillary thyroid carcinoma.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT , Carcinoma Papilar , Receptor alfa de Estrógeno , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Ubiquitina-Proteína Ligasas , Proteínas Potenciadoras de Unión a CCAAT/genética , Carcinoma Papilar/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Estrógenos , Humanos , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/genéticaRESUMEN
PES1, a BRCT domain-containing protein, has been shown to play a role in modulating the balance and ratio between ERα and ERß protein, which is involved in the occurrence and development of breast and ovarian cancer. However, its role in connection with the balance and ratio between ERα and ERß protein in papillary thyroid cancer (PTC) remains unclear. Here, we found that ERα and ERß were co-expressed in human PTC tissues and cells. ERα promoted and ERß inhibited the proliferation, invasion and migration of PTC cells. PES1 modulated the balance between ERα and ERß by elevating the ERα protein level and simultaneously reducing the ERß protein level, then upregulating the ERα/ERß protein ratio and promoting the proliferation, invasion and migration of PTC cells. In PTC tissues, PES1 protein level was positively correlated with the ERα protein level and negatively correlated with the ERß protein level. The PES1 and ERα protein levels were gradually increased and the ERß protein level was decreased by degree in the occurrence and development of PTC. Increased PES1 and ERα protein levels and decreased ERß protein level were correlated with the aggressive behaviors of PTC patients such as large tumor size, extrathyroidal extension (ETE), lymph node metastasis (LNM), high BRAFV600E expression and high TNM stage. It is suggested that PES1 promotes the occurrence and development of PTC by elevating the ERα protein level and reducing the ERß protein level, and then upregulating the ERα/ERß protein ratio.