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Cell Biosci. 2019 Jun 6;9:44. doi: 10.1186/s13578-019-0310-2. eCollection 2019.

IGFBP7 inhibits cell proliferation by suppressing AKT activity and cell cycle progression in thyroid carcinoma.

Zhang L#1,2, Lian R#1,2, Zhao J3,4, Feng X1,2, Ye R5, Pan L6, Wu J1,2, Li M1,2, Huan Y7, Cai J1.

Author information

1
1Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, 74 Zhongshan Er Road, Guangzhou, 510080 Guangdong China.
2
2Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080 Guangdong China.
3
3Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong China.
4
4NHC Key Laboratory on Assisted Circulation of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong China.
5
5Department of Breast and Thyroid Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong China.
6
6Department of Breast Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510080 Guangdong China.
7
7State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, 510000 Guangdong China.
#
Contributed equally

Abstract

Background:

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) 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.

Results:

We 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.

Conclusions:

IGFBP7 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.

KEYWORDS:

AKT; Cell cycle; IGFBP7; Proliferation; Thyroid cancer

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