Abstract
BackgroundThyroid cancer is the most common malignant endocrine tumor and is classified into papillary thyroid cancer (PTC), follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC), which have substantially different characteristics. Insulin-like growth factor binding protein 7 (IGFBP7) has recently been recognized as a tumor suppressor in many cancer types. However, the expression pattern of IGFBP7 and its biological function in various types of thyroid carcinoma remain poorly understood.ResultsWe found that the protein levels of IGFBP7 in FTC and ATC tissues were significantly lower or even absent compared with those in normal thyroid, benign thyroid adenoma and classical PTC tissues. Moreover, overexpression of IGFBP7 in two undifferentiated ATC cell lines, ARO and FRO, and one differentiated FTC cell line, WRO, significantly inhibited cell proliferation in vitro. In vivo experiments revealed that ectopic IGFBP7 expression markedly suppressed growth of tumor xenografts derived from these thyroid cancer cell lines, while IGFBP7 silencing accelerated tumor growth. At the mechanistic level, overexpression of IGFBP7 dramatically suppressed phosphorylation-mediated activation and kinase activity of AKT, causing an upregulation of cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p21Cip1 and induction of G1/S cell cycle arrest, while silencing IGFBP7 exerted the opposite effects.ConclusionsIGFBP7 expression is decreased or even absent in FTC and ATC. Acting as a cell cycle repressor, IGFBP7 plays an important tumor-suppressive role in human thyroid cancer, especially in FTC and ATC subtypes and may represent a promising biomarker and therapeutic target for human thyroid cancer treatment.
Highlights
Thyroid cancer is the most common malignant endocrine tumor and is classified into papillary thyroid cancer (PTC), follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC), which have substantially different characteristics
Insulin-like growth factor binding protein 7 (IGFBP7) expression is downregulated in the FTC and ATC subtypes of thyroid cancer To determine the protein levels of IGFBP7 in different subtypes of thyroid tumors, we employed immunohistochemical staining in our collection of 112 paraffin-embedded, archived thyroid neoplasm specimens, including 18 cases of thyroid adenoma, 63 cases of papillary thyroid carcinoma (PTC), cases of follicular thyroid carcinoma (FTC), and cases of anaplastic thyroid carcinoma (ATC)
Classical papillary thyroid carcinoma (CPTC) tissues showed much strong IGFBP7 immunostaining, whereas follicular papillary thyroid carcinoma (FVPTC) tissues hardly showed IGFBP7 expression (Fig. 1c). These data showed that the expression of IGFBP7 was significantly lower or even absent in FTC and ATC as compared with that in normal thyroid tissues, benign thyroid tumors and classical PTC, suggesting that IGFBP7 may represent a valuable biomarker for well-differentiated and poorly differentiated thyroid carcinoma
Summary
Thyroid cancer is the most common malignant endocrine tumor and is classified into papillary thyroid cancer (PTC), follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC), which have substantially different characteristics. Thyroid cancer is the most common malignant endocrine tumor. Differentiated thyroid carcinoma (DTC), including PTC and FTC, has a favorable prognosis due to slow growth, well differentiation and lowgrade malignancy. In contrast, ATC is characterized by poor differentiation and is notorious for its aggressive clinical behavior and tendency to rapidly metastasize and develop intrinsic resistance to chemotherapy, making it one of the most malignant tumors [4]. Due to the lack of effective biomarkers for well-differentiated and poorly differentiated thyroid carcinoma, inappropriate excessive treatments have been used in clinical therapy. There is an urgent need to investigate the molecular mechanisms underlying the development and progression of thyroid cancer for identifying potential molecular biomarkers to distinguish various subtypes of thyroid cancer and develop effective therapeutic strategies
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