ABSTRACT
Although thyroid cancer is the most prevalent endocrine malignancy, overall patients with thyroid cancer have a good long-term survival. However, a small percentage of patients with progressive thyroid cancer have poor outcomes, and the genetic drivers playing a key role thyroid cancer progression are mostly unknown. Here, we investigated the role of the PINX1 in thyroid cancer progression. Interestingly, PINX1 expression was significantly higher in ATC than in PTC in both patients and cell lines. When PINX1 was knockdown in ATC cells, cell proliferation rates, colony formation capacity, and cell cycle progression were significantly reduced. Furthermore, cell motility and the expression of EMT drivers were reduced by PINX1 downregulation. In contrast, the overexpression of PINX1 in PTC cells significantly increased those phenotypes of tumor progression, which demonstrates that PINX1 could promote tumor proliferation and malignant transformation in both PTC and ATC cells. To further understand whether PINX1 is also involved in the progression of PTC to ATC, we examined PI3K/AKT, MAPK, and ß-catenin signaling activation after PINX1 modulation. Decreased PINX1 expression reduced the levels of p-AKT, p-ERK, p-p38, and ß-catenin in ATC cells, but the increase of PINX1 expression upregulated the phosphorylation of AKT, ERK, and p38 and the levels of ß-catenin in PTC cells. These results were all confirmed in xenograft mouse tumors. Our findings suggest that PINX1 regulates thyroid cancer progression by promoting cell proliferation, EMT, and signaling activation, and support the hypothesis that PINX1 could be a prognostic marker and a therapeutic target of thyroid cancer.
ABSTRACT
PIN2/TERF1 interacting telomerase inhibitor 1 (PINX1) is a telomerase inhibitor located on human chromosome 8p23 and also acts as a tumor suppressor in several types of cancers, including breast, gastric, ovarian, and bladder cancer. However, the role of PINX1 expression in papillary thyroid carcinoma (PTC) has not been defined. Therefore, we investigated the role of PINX1 expression in PTC by analyzing the correlation between PINX1 expression and various clinicopathological factors. Immunohistochemistry for PINX1 was performed using a tissue microarray of samples taken from the 160 patients with PTC. We also assessed mRNA and protein expression for PINX1 via quantitative real-time polymerase chain reaction and immunohistochemical analysis. Positive staining for PINX1 was found in 16.3% of PTC cases. PINX1 expression was significantly associated with tumor size, lymph node metastasis, telomerase reverse transcriptase, promoter mutation and recurrence. PINX1 mRNA expression was more pronounced in the recurrent group than in the nonrecurrent group. In addition, results of the binary logistic regression model showed that PINX1 protein expression had a significant influence on recurrence. We concluded that PINX1 expression was associated with several clinicopathological factors and had a significant influence on recurrence in patients with PTC. Therefore, PINX1 expression could be a useful prognostic marker in PTC patients.
Subject(s)
Biomarkers, Tumor/analysis , Thyroid Cancer, Papillary/chemistry , Thyroid Neoplasms/chemistry , Tumor Suppressor Proteins/analysis , Adult , Aged , Biomarkers, Tumor/genetics , Cell Cycle Proteins , Female , Humans , Immunohistochemistry , Lymph Node Excision , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Recurrence, Local , Real-Time Polymerase Chain Reaction , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , Risk Factors , Thyroid Cancer, Papillary/genetics , Thyroid Cancer, Papillary/secondary , Thyroid Cancer, Papillary/therapy , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Thyroid Neoplasms/therapy , Thyroidectomy , Tissue Array Analysis , Treatment Outcome , Tumor Burden , Tumor Suppressor Proteins/genetics , Young AdultABSTRACT
AIMS: The Notch signalling pathway is involved in normal development as well as tumorigenesis. However, it is unclear whether Notch activation is related to diverse clinicopathological factors in papillary thyroid carcinoma (PTC). METHODS AND RESULTS: We examined the relationship between clinicopathological factors and the expression of activated Notch1 and Hey1, which are indicators of Notch signalling pathway activation, in 109 PTC cases. Activated Notch1 showed strong, moderate and weak expression in 23, 48 and 36 cases, respectively. Its expression was related significantly to histopathological variants (P = 0.007), lymph node metastasis (P = 0.016), BRAF mutation (P = 0.036) and extent of surgery (P = 0.014). Hey1 immunostaining could be divided into two groups: positive and negative, with 26 and 83 cases, respectively. Its expression was related significantly to histopathological variants (P = 0.026), extrathyroidal extension (P = 0.005), BRAF mutation (P = 0.048) and recurrence or soft tissue metastasis (P = 0.000). Multivariate analysis revealed that tumour size (>1 cm), Hey1 immunoreactivity and the presence of lymph node metastasis were associated significantly with recurrence or soft tissue metastasis (odds ratio = 7.38, 4.28 and 12.00, respectively). CONCLUSIONS: Thus, we found that activation of Notch signalling was correlated significantly with clinicopathological parameters. Therefore, Notch signalling could be a useful prognostic marker in patients with PTC.