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Down-regulation of matrix metalloproteinase-7 inhibits metastasis of human anaplastic thyroid cancer cell line

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Abstract

Epigenetic drugs such as histone deacetylase inhibitors (HDACIs) possess anticancer properties due to its ability to regulate genes associated with tumor growth, differentiation, apoptosis and metastasis. In addition to its apoptotic effect, phenylbutyrate (PB), a carboxylic acid HDACI, inhibited an anaplastic (ATC) thyroid cancer cell line ARO from penetrating a matrigel coated transwell with concomitant suppression of a metastasis-associated gene, matrix metalloproteinase-7 (MMP-7) and stimulation of a transformation suppressor protein, reversion-inducing- cysteine-rich protein with Kazal motifs without affecting MMP-2 expression levels. Direct evidence suggesting MMP-7 down-regulated cancer metastasis came from the observation of a decreased pulmonary metastasis in SCID mice xeno-transplanted with MMP-7-knocked-down ARO cells. In addition, H-89, a protein kinase A inhibitor, remarkably restored the down-regulaed MMP-7 level treated by PB. Thus, the suppressive effect of PB on MMP-7 was partially carried out through H3 phosphoacetylation. To conclude, our findings suggest PB inhibits MMP-7 expression epigenetically through phosphoacetylation of histone proteins, and thereby, reduced invasive ability of an ATC thyroid cancer cell line.

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Abbreviations

HDACI:

Histone deacetylase inhibitors

PB:

Phenylbutyrate

MMP:

Matrix metalloproteinase

RECK:

Reversion-inducing-cysteine-rich protein with Kazal motifs

TIMP:

Tissue inhibitor of MMP

siRNA:

Small interference RNA

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Acknowledgments

The authors wish to thank Dr. K. H. Lin and Dr. S. K. Liao (Chang-Gung University) for their kind supports and valuable suggestions. The authors also like to express their appreciation to Dr. C. Hsueh (Division of Pathology, Chang-Gung Memorial Hospital) for her expert review of the surgical samples. The authors would like to thank the Chang-Gung Memorial Hospital (CMRPG32046) for financially supporting this research.

Author information

Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Internal Medicine; College of Medicine, Chang-Gung University, Taoyaun, Taiwan, R.O.C

    Szu-Tah Chen, Jen-Der Lin, Yu-Yao Huang & Brend Ray-Sea Hsu

  2. Division of Thoracic and Cardiovascular Surgery, Chang-Gung Memorial Hospital; College of Medicine, Chang-Gung University, Taoyuan, Taiwan, R.O.C

    Dah-Wel Liu

  3. Division of Endocrinology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, R.O.C

    Fang-Wu Chen

  4. Division of Endocrinology and Metabolism, Chang-Gung Memorial Hospital, 5 Fushin st. Kwei-san County, Taoyaun Hsien, Taiwan, R.O.C

    Brend Ray-Sea Hsu

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  1. Szu-Tah Chen
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  2. Dah-Wel Liu
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  4. Fang-Wu Chen
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Corresponding author

Correspondence to Brend Ray-Sea Hsu.

Additional information

S.-T. Chen and D.-W. Liu contribute equally to this work.

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10585_2011_9430_MOESM1_ESM.jpg

Expression of MMP-7 identified by (a) QRT-PCR and (b) IHC in thyroid tissues. In (a), the expression levels of MMP-7 (closed symbols) and β-actin (open symbols) were estimated by relative quantitations (CT). The expression level of individual sample extracted from tumor parts of 14 PTC (●), 3 ATC (■) and 6 NG (▲) were indicated, β-actin, rather than GAPDH, was applied as internal control in this study because of its relative stability. Horizontal bars stand for the means of each of the group. In (b), the expression of MMP-7 was documented by the presence of brown-colored staining in the cytoplasm of 2 ATC (b1-2 and b3-8; respectively). Representative photographs of the tumor (b2) and the normal (b4) parts showed the magnified regions boxed in b1 and b3, respectively. The presence of MMP-7 in the invasive front of the tumor boxed in b3 was shown in b5-8. (JPG 300 kb)

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Chen, ST., Liu, DW., Lin, JD. et al. Down-regulation of matrix metalloproteinase-7 inhibits metastasis of human anaplastic thyroid cancer cell line. Clin Exp Metastasis 29, 71–82 (2012). https://doi.org/10.1007/s10585-011-9430-8

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  • DOI: https://doi.org/10.1007/s10585-011-9430-8

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