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Molecular Cancer
Published in: Molecular Cancer 1/2014

Open Access 01-12-2014 | Research

Thyroid hormone enhanced human hepatoma cell motility involves brain-specific serine protease 4 activation via ERK signaling

Authors: Cheng-Yi Chen, I-Hsiao Chung, Ming-Ming Tsai, Yi-Hsin Tseng, Hsiang-Cheng Chi, Chung-Ying Tsai, Yang-Hsiang Lin, You-Ching Wang, Chie-Pein Chen, Tzu-I Wu, Chau-Ting Yeh, Dar-In Tai, Kwang-Huei Lin

Published in: Molecular Cancer | Issue 1/2014

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Abstract

Background

The thyroid hormone, 3, 3′, 5-triiodo-L-thyronine (T3), has been shown to modulate cellular processes via interactions with thyroid hormone receptors (TRs), but the secretory proteins that are regulated to exert these effects remain to be characterized. Brain-specific serine protease 4 (BSSP4), a member of the human serine protease family, participates in extracellular matrix remodeling. However, the physiological role and underlying mechanism of T3-mediated regulation of BSSP4 in hepatocellular carcinogenesis are yet to be established.

Methods

The thyroid hormone response element was identified by reporter and chromatin immunoprecipitation assays. The cell motility was analyzed via transwell and SCID mice. The BSSP4 expression in clinical specimens was examined by Western blot and quantitative reverse transcription polymerase chain reaction.

Results

Upregulation of BSSP4 at mRNA and protein levels after T3 stimulation is a time- and dose-dependent manner in hepatoma cell lines. Additionally, the regulatory region of the BSSP4 promoter stimulated by T3 was identified at positions -609/-594. BSSP4 overexpression enhanced tumor cell migration and invasion, both in vitro and in vivo. Subsequently, BSSP4-induced migration occurs through the ERK 1/2-C/EBPβ-VEGF cascade, similar to that observed in HepG2-TRα1 and J7-TRα1 cells. BSSP4 was overexpressed in clinical hepatocellular carcinoma (HCC) patients, compared with normal subjects, and positively associated with TRα1 and VEGF to a significant extent. Importantly, a mild association between BSSP4 expression and distant metastasis was observed.

Conclusions

Our findings collectively support a potential role of T3 in cancer cell progression through regulation of the BSSP4 protease via the ERK 1/2-C/EBPβ-VEGF cascade. BSSP4 may thus be effectively utilized as a novel marker and anti-cancer therapeutic target in HCC.
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Literature
1.
2.
Chen CY, Tsai MM, Chi HC, Lin KH: Biological significance of a thyroid hormone-regulated secretome. Biochim Biophys Acta. 2013, 1834: 2271-2284.CrossRefPubMed
3.
Huang YH, Tsai MM, Lin KH: Thyroid hormone dependent regulation of target genes and their physiological significance. Chang Gung Med J. 2008, 31: 325-334.PubMed
4.
Wu SM, Cheng WL, Lin CD, Lin KH: Thyroid hormone actions in liver cancer. Cell Mol Life Sci. 2013, 70: 1915-1936.CrossRefPubMed
5.
Chen CY, Chi LM, Chi HC, Tsai MM, Tsai CY, Tseng YH, Lin YH, Chen WJ, Huang YH, Lin KH: Stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics study of a thyroid hormone-regulated secretome in human hepatoma cells. Mol Cell Proteomics. 2012, 11: M111-011270,CrossRef
6.
Yasuda S, Morokawa N, Wong GW, Rossi A, Madhusudhan MS, Sali A, Askew YS, Adachi R, Silverman GA, Krilis SA, Stevens RL: Urokinase-type plasminogen activator is a preferred substrate of the human epithelium serine protease tryptase epsilon/PRSS22. Blood. 2005, 105: 3893-3901.PubMedCentralCrossRefPubMed
7.
Wong GW, Yasuda S, Madhusudhan MS, Li L, Yang Y, Krilis SA, Sali A, Stevens RL: Human tryptase epsilon (PRSS22), a new member of the chromosome 16p13.3 family of human serine proteases expressed in airway epithelial cells. J Biol Chem. 2001, 276: 49169-49182.CrossRefPubMed
8.
Dass K, Ahmad A, Azmi AS, Sarkar SH, Sarkar FH: Evolving role of uPA/uPAR system in human cancers. Cancer Treat Rev. 2008, 34: 122-136.CrossRefPubMed
9.
Mitsui S, Okui A, Kominami K, Konishi E, Uemura H, Yamaguchi N: A novel serine protease highly expressed in the pancreas is expressed in various kinds of cancer cells. FEBS J. 2005, 272: 4911-4923.CrossRefPubMed
10.
Hofmann UB, Eggert AA, Blass K, Brocker EB, Becker JC: Expression of matrix metalloproteinases in the microenvironment of spontaneous and experimental melanoma metastases reflects the requirements for tumor formation. Cancer Res. 2003, 63: 8221-8225.PubMed
11.
Peinado H, Portillo F, Cano A: Transcriptional regulation of cadherins during development and carcinogenesis. Int J Dev Biol. 2004, 48: 365-375.CrossRefPubMed
12.
Lin Z, Crockett DK, Jenson SD, Lim MS, Elenitoba-Johnson KS: Quantitative proteomic and transcriptional analysis of the response to the p38 mitogen-activated protein kinase inhibitor SB203580 in transformed follicular lymphoma cells. Mol Cell Proteomics. 2004, 3: 820-833.CrossRefPubMed
13.
Celis JE, Moreira JM, Cabezon T, Gromov P, Friis E, Rank F, Gromova I: Identification of extracellular and intracellular signaling components of the mammary adipose tissue and its interstitial fluid in high risk breast cancer patients: toward dissecting the molecular circuitry of epithelial-adipocyte stromal cell interactions. Mol Cell Proteomics. 2005, 4: 492-522.CrossRefPubMed
14.
Yoon SY, Lee YJ, Seo JH, Sung HJ, Park KH, Choi IK, Kim SJ, Oh SC, Choi CW, Kim BS, Shin SW, Kim YH, Kim JS: uPAR expression under hypoxic conditions depends on iNOS modulated ERK phosphorylation in the MDA-MB-231 breast carcinoma cell line. Cell Res. 2006, 16: 75-81.CrossRefPubMed
15.
Wei F, Yan J, Tang D: Extracellular signal-regulated kinases modulate DNA damage response - a contributing factor to using MEK inhibitors in cancer therapy. Curr Med Chem. 2011, 18: 5476-5482.PubMedCentralCrossRefPubMed
16.
Clarke DN, Al Ahmad A, Lee B, Parham C, Auckland L, Fertala A, Kahle M, Shaw CS, Roberts J, Bix GJ: Perlecan Domain V induces VEGf secretion in brain endothelial cells through integrin alpha5beta1 and ERK-dependent signaling pathways. PLoS One. 2012, 7: e45257-PubMedCentralCrossRefPubMed
17.
Rajcevic U, Petersen K, Knol JC, Loos M, Bougnaud S, Klychnikov O, Li KW, Pham TV, Wang J, Miletic H, Peng Z, Bjerkvig R, Jimenez CR, Niclou SP: iTRAQ-based proteomics profiling reveals increased metabolic activity and cellular cross-talk in angiogenic compared with invasive glioblastoma phenotype. Mol Cell Proteomics. 2009, 8: 2595-2612.PubMedCentralCrossRefPubMed
18.
Tsukada J, Yoshida Y, Kominato Y, Auron PE: The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation. Cytokine. 2011, 54: 6-19.CrossRefPubMed
19.
Doerig C, Billker O, Pratt D, Endicott J: Protein kinases as targets for antimalarial intervention: Kinomics, structure-based design, transmission-blockade, and targeting host cell enzymes. Biochim Biophys Acta. 2005, 1754: 132-150.CrossRefPubMed
20.
Tong C, Fan HY, Chen DY, Song XF, Schatten H, Sun QY: Effects of MEK inhibitor U0126 on meiotic progression in mouse oocytes: microtuble organization, asymmetric division and metaphase II arrest. Cell Res. 2003, 13: 375-383.CrossRefPubMed
21.
Gomis-Ruth FX: Structural aspects of the metzincin clan of metalloendopeptidases. Mol Biotechnol. 2003, 24: 157-202.CrossRefPubMed
22.
Uria JA, Werb Z: Matrix metalloproteinases and their expression in mammary gland. Cell Res. 1998, 8: 187-194.CrossRefPubMed
23.
Xu D, Suenaga N, Edelmann MJ, Fridman R, Muschel RJ, Kessler BM: Novel MMP-9 substrates in cancer cells revealed by a label-free quantitative proteomics approach. Mol Cell Proteomics. 2008, 7: 2215-2228.PubMedCentralCrossRefPubMed
24.
25.
Meng YG, Han WD, Zhao YL, Huang K, Si YL, Wu ZQ, Mu YM: Induction of the LRP16 gene by estrogen promotes the invasive growth of Ishikawa human endometrial cancer cells through the downregulation of E-cadherin. Cell Res. 2007, 17: 869-880.CrossRefPubMed
26.
Xu J, Lamouille S, Derynck R: TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009, 19: 156-172.CrossRefPubMed
27.
Yang J, Eddy JA, Pan Y, Hategan A, Tabus I, Wang Y, Cogdell D, Price ND, Pollock RE, Lazar AJ, Hunt KK, Trent JC, Zhang W: Integrated proteomics and genomics analysis reveals a novel mesenchymal to epithelial reverting transition in leiomyosarcoma through regulation of slug. Mol Cell Proteomics. 2010, 9: 2405-2413.PubMedCentralCrossRefPubMed
28.
29.
Chang SH, Kanasaki K, Gocheva V, Blum G, Harper J, Moses MA, Shih SC, Nagy JA, Joyce J, Bogyo M, Kalluri R, Dvorak HF: VEGF-A induces angiogenesis by perturbing the cathepsin-cysteine protease inhibitor balance in venules, causing basement membrane degradation and mother vessel formation. Cancer Res. 2009, 69: 4537-4544.PubMedCentralCrossRefPubMed
30.
Kulasingam V, Diamandis EP: Proteomics analysis of conditioned media from three breast cancer cell lines: a mine for biomarkers and therapeutic targets. Mol Cell Proteomics. 2007, 6: 1997-2011.CrossRefPubMed
31.
Huang Y, Hua K, Zhou X, Jin H, Chen X, Lu X, Yu Y, Zha X, Feng Y: Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma. Cell Res. 2008, 18: 780-791.CrossRefPubMed
32.
Roudnicky F, Poyet C, Wild P, Krampitz S, Negrini F, Huggenberger R, Rogler A, Stohr R, Hartmann A, Provenzano M, Otto VI, Detmar M: Endocan is upregulated on tumor vessels in invasive bladder cancer where it mediates VEGF-A-induced angiogenesis. Cancer Res. 2013, 73: 1097-1106.CrossRefPubMed
33.
Yen CJ, Lin YJ, Yen CS, Tsai HW, Tsai TF, Chang KY, Huang WC, Lin PW, Chiang CW, Chang TT: Hepatitis B virus X protein upregulates mTOR signaling through IKKbeta to increase cell proliferation and VEGF production in hepatocellular carcinoma. PLoS One. 2012, 7: e41931-PubMedCentralCrossRefPubMed
34.
Poli V: The role of C/EBP isoforms in the control of inflammatory and native immunity functions. J Biol Chem. 1998, 273: 29279-29282.CrossRefPubMed
35.
Sebastian T, Johnson PF: RasV12-mediated down-regulation of CCAAT/enhancer binding protein beta in immortalized fibroblasts requires loss of p19Arf and facilitates bypass of oncogene-induced senescence. Cancer Res. 2009, 69: 2588-2598.PubMedCentralCrossRefPubMed
36.
Cui TX, Lin G, LaPensee CR, Calinescu AA, Rathore M, Streeter C, Piwien-Pilipuk G, Lanning N, Jin H, Carter-Su C, Qin ZS, Schwartz J: C/EBPbeta mediates growth hormone-regulated expression of multiple target genes. Mol Endocrinol. 2011, 25: 681-693.PubMedCentralCrossRefPubMed
37.
Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS: Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008, 133: 1019-1031.CrossRefPubMed
38.
Olazabal IM, Munoz JA, Rodriguez-Navas C, Alvarez L, Delgado-Baeza E, Garcia-Ruiz JP: Prolactin’s role in the early stages of liver regeneration in rats. J Cell Physiol. 2009, 219: 626-633.CrossRefPubMed
39.
Montano MM, Doughman YQ, Deng H, Chaplin L, Yang J, Wang N, Zhou Q, Ward NL, Watanabe M: Mutation of the HEXIM1 gene results in defects during heart and vascular development partly through downregulation of vascular endothelial growth factor. Circ Res. 2008, 102: 415-422.PubMedCentralCrossRefPubMed
40.
Shen K, Ji L, Gong C, Ma Y, Yang L, Fan Y, Hou M, Wang Z: Notoginsenoside Ft1 promotes angiogenesis via HIF-1alpha mediated VEGF secretion and the regulation of PI3K/AKT and Raf/MEK/ERK signaling pathways. Biochem Pharmacol. 2012, 84: 784-792.CrossRefPubMed
41.
Feng J, Zhang Y, Xing D: Low-power laser irradiation (LPLI) promotes VEGF expression and vascular endothelial cell proliferation through the activation of ERK/Sp1 pathway. Cell Signal. 2012, 24: 1116-1125.CrossRefPubMed
42.
Chen RN, Huang YH, Lin YC, Yeh CT, Liang Y, Chen SL, Lin KH: Thyroid hormone promotes cell invasion through activation of furin expression in human hepatoma cell lines. Endocrinology. 2008, 149: 3817-3831.PubMedCentralCrossRefPubMed
43.
Chen RN, Huang YH, Yeh CT, Liao CH, Lin KH: Thyroid hormone receptors suppress pituitary tumor transforming gene 1 activity in hepatoma. Cancer Res. 2008, 68: 1697-1706.CrossRefPubMed
44.
Samuels HH, Stanley F, Casanova J: Depletion of L-3, 5, 3′-triiodothyronine and L-thyroxine in euthyroid calf serum for use in cell culture studies of the action of thyroid hormone. Endocrinology. 1979, 105: 80-85.CrossRefPubMed
45.
Liao CH, Yeh SC, Huang YH, Chen RN, Tsai MM, Chen WJ, Chi HC, Tai PJ, Liao CJ, Wu SM, Cheng WL, Pai LM, Lin KH: Positive regulation of spondin 2 by thyroid hormone is associated with cell migration and invasion. Endocr Relat Cancer. 2010, 17: 99-111.CrossRefPubMed
46.
Wu SM, Huang YH, Lu YH, Chien LF, Yeh CT, Tsai MM, Liao CH, Chen WJ, Liao CJ, Cheng WL, Lin KH: Thyroid hormone receptor-mediated regulation of the methionine adenosyltransferase 1 gene is associated with cell invasion in hepatoma cell lines. Cell Mol Life Sci. 2010, 67: 1831-1843.CrossRefPubMed
47.
Huang YH, Lee CY, Tai PJ, Yen CC, Liao CY, Chen WJ, Liao CJ, Cheng WL, Chen RN, Wu SM, Wang CS, Lin KH: Indirect regulation of human dehydroepiandrosterone sulfotransferase family 1A member 2 by thyroid hormones. Endocrinology. 2006, 147: 2481-2489.CrossRefPubMed
48.
Repesh LA: A new in vitro assay for quantitating tumor cell invasion. Invasion Metastasis. 1989, 9: 192-208.PubMed
Metadata
Title
Thyroid hormone enhanced human hepatoma cell motility involves brain-specific serine protease 4 activation via ERK signaling
Authors
Cheng-Yi Chen
I-Hsiao Chung
Ming-Ming Tsai
Yi-Hsin Tseng
Hsiang-Cheng Chi
Chung-Ying Tsai
Yang-Hsiang Lin
You-Ching Wang
Chie-Pein Chen
Tzu-I Wu
Chau-Ting Yeh
Dar-In Tai
Kwang-Huei Lin
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-13-162

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