Down‐regulation of FOXR2 inhibits hypoxia‐driven ROS‐induced migration and invasion of thyroid cancer cells via regulation of the hedgehog pathway

Context: ZIC1 has been reported to be overexpressed and plays an oncogenic role in some brain tumors, whereas it is inactivated by promoter hypermethylation and acts as a tumor suppressor in gastric and colorectal cancers. However, until now, its biological role in thyroid cancer remains totally unknown. Objectives: The aim of this study is to explore the biological functions and related molecular mechanism of ZIC1 in thyroid carcinogenesis. Setting and Design: Quantitative RT-PCR (qRT-PCR) was performed to evaluate mRNA expression of investigated genes. Methylation-specific PCR was used to analyze promoter methylation of the ZIC1 gene. The functions of ectopic ZIC1 expression in thyroid cancer cells were determined by cell proliferation and colony formation, cell cycle and apoptosis, as well as cell migration and invasion assays. Results: ZIC1 was frequently down-regulated by promoter hypermethylation in both primary thyroid cancer tissues and thyroid cancer cell lines. Moreover, our data showed that ZIC1 hypermethylation was significantly associated with lymph node metastasis in patients with papillary thyroid cancer. Notably, restoration of ZIC1 expression in thyroid cancer cells dramatically inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrest and apoptosis by blocking the activities of the phosphatidylinositol-3-kinase (PI3K)/Akt and RAS/RAF/MEK/ERK (MAPK) pathways, and enhancing FOXO3a transcriptional activity. Conclusions: Our data demonstrate that ZIC1 is frequently inactivated by promoter hypermethyaltion and functions as a tumor suppressor in thyroid cancer through modulating PI3K/Akt and MAPK signaling pathways and transcription factor FOXO3a.

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Shikonin Inhibites Migration and Invasion of Thyroid Cancer Cells by Downregulating DNMT1

Medical Science Monitor ◽

10.12659/msm.908381 ◽

2018 ◽

Vol 24 ◽

pp. 661-670 ◽

Cited By ~ 10

Author(s):

Yue Zhang ◽

Bin Sun ◽

Zhi Huang ◽

Dai-Wei Zhao ◽

Qingfan Zeng

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Migration And Invasion ◽

Thyroid Cancer Cells

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Tamoxifen inhibits growth, migration, and invasion of human follicular and papillary thyroid cancer cells in vitro and in vivo.

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.80.1.7829632 ◽

1995 ◽

Vol 80 (1) ◽

pp. 308-313

Author(s):

T Hoelting ◽

A E Siperstein ◽

Q Y Duh ◽

O H Clark

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Papillary Thyroid Cancer ◽

Migration And Invasion ◽

Papillary Thyroid ◽

Thyroid Cancer Cells

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Synergistic Antitumor Effect of BKM120 with Prima-1Met Via Inhibiting PI3K/AKT/mTOR and CPSF4/hTERT Signaling and Reactivating Mutant P53

Cellular Physiology and Biochemistry ◽

10.1159/000487786 ◽

2018 ◽

Vol 45 (5) ◽

pp. 1772-1786 ◽

Cited By ~ 9

Author(s):

Zongjuan Li ◽

Xiangdong Xu ◽

Yizhuo Li ◽

Kun Zou ◽

Zhuo Zhang ◽

...

Keyword(s):

Thyroid Cancer ◽

Cell Viability ◽

Cancer Cells ◽

Colony Formation ◽

Antitumor Effect ◽

Migration And Invasion ◽

Mutant P53 ◽

Stem Cell Markers ◽

Combinational Treatment ◽

Thyroid Cancer Cells

Background/Aims: PI3KCA and mutant p53 are associated with tumorigenesis and the development of cancers. NVP-BKM120, a selective pan-PI3K inhibitor, exerts the antitumor activity by suppressing the PI3K signaling pathway. Prima-1Met, a low molecular weight compound, can rescue the gain-of-function of mutant p53 by restoring its transcriptional function. In this study, we investigated whether PI3K inhibition combined with mutant p53 reactivation could enhance the antitumor effect in thyroid cancer cells. Methods: The effects of BKM120 and Prima-1Met on the proliferation, apoptosis, migration and invasion of thyroid cancer cells were measured by MTT, colony formation, flow cytometry, wound-healing and transwell assays, respectively. Thyroid differentiation was assessed by detecting the expression levels of specific markers using RT-PCR and Western blot. The in vivo antitumor efficacy was analyzed in a mouse xenograft model. Results: The combinational treatment of BKM120 and Prima-1Met significantly enhanced the inhibitions of cell viability, colony formation, migration and invasion, and the induction of apoptosis in thyroid cell lines, and synergistically suppressed tumor xenograft growth by inhibiting the PI3K/Akt/mTOR and EMT signaling pathways, up-regulating p53 targeted genes, and triggering the release of cytochrome c. Moreover, the combination of BKM120 and Prima-1Met suppressed the stemlike traits of thyroid cancer cells and promoted their differentiation by upregulating the expression of thyroid-specific differentiation markers and repressing the expression of cancer stem cell markers. Furthermore, the mechanism study demonstrated that the combinational treatment synergistically abrogated the binding of CPSF4 at the promoter of hTERT and thus suppressed hTERT expression. Consistently, overexpression of hTERT rescued the inhibitions of cell viability, invasion and stem-like traits mediated by the combination of BKM120 and Prima-1Met. Conclusion: Our results showed that the combination of BKM120 with Prima-1Met synergistically suppressed the growth of thyroid cancer cells and tumor xenografts via inhibiting PI3K/Akt/mTOR and CPSF4/hTERT signaling and reactivating mutant p53.

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