This study aimed to examine HIF-2α, TWIST, and CXCR4 expression in papillary thyroid carcinoma (PTC) and assesses the association of their expression with clinicopathological indicators. HIF-2α, TWIST, and CXCR4 protein expression in 129 PTCs, 61 nodular hyperplasia, and 118 normal thyroid tissue specimens was analyzed using immunohistochemistry. The protein expression levels of these three molecules were upregulated in PTCs. High protein expression of HIF-2α, TWIST, and CXCR4 was significantly correlated with lymph node metastasis (LNM) (P<0.001). Furthermore, HIF-2α, TWIST, and CXCR4 protein expression was correlated with one another. Concomitant high expression of these molecules had stronger correlation with LNM than did each alone (P=0.032for HIF-2α/TWIST,P<0.001for HIF-2α/CXCR4,P=0.018for TWIST/CXCR4, andP<0.001for HIF-2α/TWIST/CXCR4). Additionally, HIF-2α, TWIST, and CXCR4 mRNA expression were assessed in 30 PTCs, 10 nodular hyperplasia, and 10 normal thyroid tissue specimens using real-time RT-PCR. TWIST and CXCR4 mRNA expression levels were up-regulated in PTCs, and high mRNA expression of TWIST and CXCR4 was significantly correlated with LNM (P=0.005andP=0.010, resp.). These results demonstrated that the evaluation of HIF-2α, TWIST, and CXCR4 expression in PTC may be useful in predicting the risk of LNM.

ERα, ERβ, PR, ERα36, EGFR and HER2 mRNA and protein expression in papillary thyroid carcinoma (PTC) were examined by real time RT-PCR and immunohistochemical staining. The mRNA and protein expression of ERα and PR were gradually increased and those of ERβ were gradually decreased from normal thyroid tissues to nodular hyperplasias (P < 0.05) and to PTCs (P < 0.05). However, the mRNA and protein expression of ERα36, EGFR and HER2 were only significantly increased in PTCs when compared with those in normal thyroid tissues (P < 0.001) and nodular hyperplasias (P < 0.001). There was some correlation between ERα, ERβ and PR, and between ERα36, EGFR and HER2 protein expression in PTCs. As for ERα, ERβ and PR, there was a significant positive correlation between ERα and PR, and a significant negative correlation between ERα and ERβ and between PR and ERβ protein expression. As for ERα36, EGFR and HER2, there was a significant positive correlation between ERα36, EGFR and HER2 protein expression in PTCs. Concomitant high expression of ERα36, EGFR and HER2 was strongly associated with aggressive behaviors including extrathyroidal extension (ETE), lymph node metastasis (LNM) and high TNM stage in PTCs (P < 0.001).

PES1, a BRCT domain-containing protein, has been shown to play a role in modulating the balance and ratio between ERα and ERβ 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 ERβ protein in papillary thyroid cancer (PTC) remains unclear. Here, we found that ERα and ERβ were co-expressed in human PTC tissues and cells. ERα promoted and ERβ inhibited the proliferation, invasion and migration of PTC cells. PES1 modulated the balance between ERα and ERβ by elevating the ERα protein level and simultaneously reducing the ERβ protein level, then upregulating the ERα/ERβ 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 ERβ protein level. The PES1 and ERα protein levels were gradually increased and the ERβ protein level was decreased by degree in the occurrence and development of PTC. Increased PES1 and ERα protein levels and decreased ERβ 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 ERβ protein level, and then upregulating the ERα/ERβ protein ratio.