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Cited by 36Thyroid Cancer Diagnosis and TreatmentThyroid Disorders and TreatmentsHepatocellular Carcinoma Treatment and Prognosis

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

Open access
Zhang, Le, Lian, Rong, Zhao, Jingjing, Feng, Xianming, Ye, Runyi, Pan, Lingxiao, Wu, Jueheng, Li, Mengfeng, Huang, Yongbo, Cai, Junchao·2019·Cell & Bioscience
DOI 10.1186/s13578-019-0310-2PMC PMC6555742
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Abstract

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. 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 p27 Kip1 and p21 Cip1 and induction of G1/S cell cycle arrest, while silencing IGFBP7 exerted the opposite effects. 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.

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Figures

Fig. 1 IGFBP7 is downregulated in human thyroid cancer samples. a Representative images of IGFBP7 immunostaining in normal thyroid tissue, thyroid adenoma and thyroid carcinoma specimens with different pathological characteristics. b Statistical analysis of the proportions of negative or positive IGFBP7 expression in clinical specimens of thyroid adenoma and thyroid carcinoma with different pathological subtypes. c Representative images of IGFBP7 immunostaining in two different papillary thyroid cancer (CPTC/FPTC) tissues
Fig. 1 IGFBP7 is downregulated in human thyroid cancer samples. a Representative images of IGFBP7 immunostaining in normal thyroid tissue, thyroid adenoma and thyroid carcinoma specimens with different pathological characteristics. b Statistical analysis of the proportions of negative or positive IGFBP7 expression in clinical specimens of thyroid adenoma and thyroid carcinoma with different pathological subtypes. c Representative images of IGFBP7 immunostaining in two different papillary thyroid cancer (CPTC/FPTC) tissuesCC BY · PubMed Central
Fig. 2 IGFBP7 exerts potent inhibitory effects on proliferation of ATC and FTC cell lines in vitro. a Western blotting assay validated the protein levels of IGFBP7 in ARO, FRO, and WRO cell lines overexpressed or silenced with IGFBP7. α-tubulin was used as a loading control. b–d Representative images and quantitation of IGFBP7-overexpressed or silenced cells at the indicated time points following initially plating the same number of cells. e MTT assay was conducted to measure the effect of IGFBP7 on the proliferation of the indicated cells at the indicated time points. f Representative micrographs (left) and relative quantification (right) of the indicated cells as evaluated by soft agar assay. All experiments were repeated three times with similar results. Data represent the mean ± S.D. of three independent experiments. A two-tailed Student’s t-test was used for statistical analysis (*P < 0.05, **P < 0.01)
Fig. 2 IGFBP7 exerts potent inhibitory effects on proliferation of ATC and FTC cell lines in vitro. a Western blotting assay validated the protein levels of IGFBP7 in ARO, FRO, and WRO cell lines overexpressed or silenced with IGFBP7. α-tubulin was used as a loading control. b–d Representative images and quantitation of IGFBP7-overexpressed or silenced cells at the indicated time points following initially plating the same number of cells. e MTT assay was conducted to measure the effect of IGFBP7 on the proliferation of the indicated cells at the indicated time points. f Representative micrographs (left) and relative quantification (right) of the indicated cells as evaluated by soft agar assay. All experiments were repeated three times with similar results. Data represent the mean ± S.D. of three independent experiments. A two-tailed Student’s t-test was used for statistical analysis (*P < 0.05, **P < 0.01)CC BY · PubMed Central
Fig. 3 IGFBP7 suppresses tumor growth in vivo. a Quantitative analysis of tumor volumes of the indicated cell xenografts at the indicated time points. b Representative image of subcutaneous tumors isolated from nude mice at the experimental endpoint (upper) and quantitative analysis of tumor weights of the indicated cell xenografts (lower). c Tumor tissue sections from the indicated cell xenografts were prepared and proceeded for H&E staining and anti-Ki-67 immunostaining. A two-tailed Student’s t-test was used for statistical analysis (*P < 0.05, **P < 0.01)
Fig. 3 IGFBP7 suppresses tumor growth in vivo. a Quantitative analysis of tumor volumes of the indicated cell xenografts at the indicated time points. b Representative image of subcutaneous tumors isolated from nude mice at the experimental endpoint (upper) and quantitative analysis of tumor weights of the indicated cell xenografts (lower). c Tumor tissue sections from the indicated cell xenografts were prepared and proceeded for H&E staining and anti-Ki-67 immunostaining. A two-tailed Student’s t-test was used for statistical analysis (*P < 0.05, **P < 0.01)CC BY · PubMed Central
Fig. 4 IGFBP7 upregulates expression of p21Cip1 and p27Kip1 and induces G1-S arrest. a Western blotting analysis of levels of p21Cip1, p27Kip1, CDK2, cyclin E, phosphorylated Rb (p-Rb, Ser780) and total Rb in the indicated cells. α-tubulin was used as a loading control. b, c Representative micrographs (upper) and quantification of the proportions (lower) of BrdU incorporating cells in IGFBP7-overexpressed or-silenced cells, as well as corresponding vector-control cells. d Flow cytometric analysis of the indicated thyroid cancer cell lines with IGFBP7 overexpression or knock down. Data represent the mean ± S.D. of three independent experiments. * P < 0.05, ** P < 0.01
Fig. 4 IGFBP7 upregulates expression of p21Cip1 and p27Kip1 and induces G1-S arrest. a Western blotting analysis of levels of p21Cip1, p27Kip1, CDK2, cyclin E, phosphorylated Rb (p-Rb, Ser780) and total Rb in the indicated cells. α-tubulin was used as a loading control. b, c Representative micrographs (upper) and quantification of the proportions (lower) of BrdU incorporating cells in IGFBP7-overexpressed or-silenced cells, as well as corresponding vector-control cells. d Flow cytometric analysis of the indicated thyroid cancer cell lines with IGFBP7 overexpression or knock down. Data represent the mean ± S.D. of three independent experiments. * P < 0.05, ** P < 0.01CC BY · PubMed Central
Fig. 5 IGFBP7 inhibits the phosphorylation and kinase activity of AKT. a Western blotting analysis of phosphorylated AKT (Ser 473 and Thr 308) and total AKT in the indicated cells. α-tubulin was used as a loading control. b The AKT kinase assay measuring AKT activity in vitro was performed. Western blotting analysis of p-GSK-3β (Ser21/9) and total AKT in the indicated cells. All data were obtained from three independent experiments with similar results
Fig. 5 IGFBP7 inhibits the phosphorylation and kinase activity of AKT. a Western blotting analysis of phosphorylated AKT (Ser 473 and Thr 308) and total AKT in the indicated cells. α-tubulin was used as a loading control. b The AKT kinase assay measuring AKT activity in vitro was performed. Western blotting analysis of p-GSK-3β (Ser21/9) and total AKT in the indicated cells. All data were obtained from three independent experiments with similar resultsCC BY · PubMed Central

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  1. Serres MP, Besson A. Critical role for p27 in mediating the antitumoral activity of a proteasome inhibitor. Med Sci. 2009;25(3):213–4.

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Metadata

Authors
Zhang, L., Lian, R., Zhao, J., Feng, X., Ye, R., Pan, L., Wu, J., Li, M., Huang, Y., & Cai, J.
Affiliations
  • Sun Yat-sen University (CN)
  • First Affiliated Hospital of Guangzhou Medical University (CN)
Corresponding author
  • Huang, Yongbo
  • Cai, Junchao
ORCID
Venue
Cell & Bioscience
Publisher
Springer Science and Business Media LLC
Published
2019-06-06
Volume
9
Issue
1
Pages
44-44
ISSN
2045-3701 (ISSN-L)
DOI
10.1186/s13578-019-0310-2
PMC
PMC6555742
OpenAlex
W2948798348
Cited by
36
References
49
Citations by year
2026: 3 · 2025: 2 · 2024: 6 · 2023: 5 · 2022: 2 · 2021: 8 · 2020: 7 · 2019: 3
FWCI
4.06
Type
journal article
Language
en
Update notices
correction (2019-07-15)
Open access
Licence
Locations
  • Cell & Bioscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Key Research and Development Program of China (2017YFA0106300)
  • the Natural Science Foundation of China (81870069, 81500279, 81772473, 81472351)
  • the Natural Science Foundation of Guangdong Province (2016A030306026)
  • Pearl River S&T Nova Program of Guangzhou (201610010177)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
IGFBP7, thyroid cancer, follicular thyroid carcinoma, anaplastic thyroid carcinoma, papillary thyroid carcinoma, Akt signaling, cell cycle arrest, G1/S cell cycle arrest, p27, p21, cyclin-dependent kinase inhibitors, tumor suppressor, cell proliferation, tumor xenografts, biomarkers, therapeutic target

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