Arachidonate 5 lipoxygenase expression in papillary thyroid carcinoma promotes invasion via MMP‐9 induction

Arachidonate 5‐lipoxygenase (ALOX5) expression and activity has been implicated in tumor pathogenesis, yet its role in papillary thyroid carcinoma (PTC) has not been characterized. ALOX5 protein and mRNA were upregulated in PTC compared to matched, normal thyroid tissue, and ALOX5 expression correlated with invasive tumor histopathology. Evidence suggests that PTC invasion is mediated through the induction of matrix metalloproteinases (MMPs) that can degrade and remodel the extracellular matrix (ECM). A correlation between MMP‐9 and ALOX5 protein expression was established by immunohistochemical analysis of PTC and normal thyroid tissues using a tissue array. Transfection of ALOX5 into a PTC cell line (BCPAP) increased MMP‐9 secretion and cell invasion across an ECM barrier. The ALOX5 product, 5(S)‐hydroxyeicosatetraenoic acid also increased MMP‐9 protein expression by BCPAP in a dose‐dependent manner. Inhibitors of MMP‐9 and ALOX5 reversed ALOX5‐enhanced invasion. Here we describe a new role for ALOX5 as a mediator of invasion via MMP‐9 induction; this ALOX5/MMP9 pathway represents a new avenue in the search for functional biomarkers and/or potential therapeutic targets for aggressive PTC. J. Cell. Biochem. 113: 1998–2008, 2012. © 2012 Wiley Periodicals, Inc.

[1]  I. Shureiqi,et al.  Determination of endogenous tissue inflammation profiles by LC/MS/MS: COX- and LOX-derived bioactive lipids. , 2006, Prostaglandins, leukotrienes, and essential fatty acids.

[2]  G. Weissmann,et al.  Integrin-dependent homotypic adhesion of neutrophils. Arachidonic acid activates Raf-1/Mek/Erk via a 5-lipoxygenase- dependent pathway. , 1998, The Journal of clinical investigation.

[3]  J. Westermarck,et al.  Regulation of matrix metalloproteinase expression in tumor invasion , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  D. Tscharke,et al.  The vaccinia virus kelch-like protein C2L affects calcium-independent adhesion to the extracellular matrix and inflammation in a murine intradermal model. , 2003, The Journal of general virology.

[5]  Editors , 1986, Brain Research Bulletin.

[6]  M. Kruhøffer,et al.  The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. , 2005, The Journal of clinical investigation.

[7]  G. Bokoch,et al.  Effect of various lipoxygenase metabolites of arachidonic acid on degranulation of polymorphonuclear leukocytes. , 1981, The Journal of biological chemistry.

[8]  J. Ghosh.  Inhibition of arachidonate 5-lipoxygenase triggers prostate cancer cell death through rapid activation of c-Jun N-terminal kinase. , 2003, Biochemical and biophysical research communications.

[9]  J. Uhm,et al.  Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. , 1996, Annals of neurology.

[10]  T. Adrian,et al.  The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells. , 2002, Biochemical and biophysical research communications.

[11]  M. Roudebush,et al.  Dominant inhibitory Ras mutants demonstrate the requirement for Ras activity in the action of tyrosine kinase oncogenes. , 1991, Oncogene.

[12]  Inge Nelissen,et al.  Gelatinase B functions as regulator and effector in leukocyte biology , 2001, Journal of leukocyte biology.

[13]  Motoharu Seiki,et al.  A matrix metalloproteinase expressed on the surface of invasive tumour cells , 1994, Nature.

[14]  M. Saji,et al.  Molecular mechanisms involved in differentiated thyroid cancer invasion and metastasis , 2007, Current opinion in oncology.

[15]  K. Entian,et al.  The 5-Lipoxygenase Promoter Is Regulated by DNA Methylation* , 2002, The Journal of Biological Chemistry.

[16]  T. Brock,et al.  Multiple Nuclear Localization Sequences Allow Modulation of 5‐Lipoxygenase Nuclear Import , 2004, Traffic.

[17]  G. Rao,et al.  5(S)-Hydroxyeicosatetraenoic Acid Stimulates DNA Synthesis in Human Microvascular Endothelial Cells via Activation of Jak/STAT and Phosphatidylinositol 3-Kinase/Akt Signaling, Leading to Induction of Expression of Basic Fibroblast Growth Factor 2* , 2002, The Journal of Biological Chemistry.

[18]  J. Drazen,et al.  Egr-1 and Sp1 interact functionally with the 5-lipoxygenase promoter and its naturally occurring mutants. , 1998, American journal of respiratory cell and molecular biology.

[19]  C. Myers,et al.  Arachidonic acid stimulates prostate cancer cell growth: critical role of 5-lipoxygenase. , 1997, Biochemical and biophysical research communications.

[20]  D. Steinhilber,et al.  On the expression and regulation of 5-lipoxygenase in human lymphocytes. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Peters-Golden,et al.  Nuclear localization of 5-lipoxygenase as a determinant of leukotriene B4 synthetic capacity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R. Muschel,et al.  Mr 92,000 gelatinase release correlates with the metastatic phenotype in transformed rat embryo cells. , 1990, Cancer research.

[23]  T. Moody,et al.  Five‐lipoxygenase inhibitors can mediate apoptosis in human breast cancer cell lines through complex eicosanoid interactions , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  T. Adrian,et al.  Multiple Signal Pathways Are Involved in the Mitogenic Effect of 5(S)-HETE in Human Pancreatic Cancer , 2003, Oncology.

[25]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[26]  L. Matrisian,et al.  Changing views of the role of matrix metalloproteinases in metastasis. , 1997, Journal of the National Cancer Institute.

[27]  N. Roehm,et al.  An improved colorimetric assay for cell proliferation and viability utilizing the tetrazolium salt XTT. , 1991, Journal of immunological methods.

[28]  J. Salmon,et al.  Inhibition of arachidonic acid cyclo-oxygenase and lipoxygenase activities of leukocytes by indomethacin and compound BW755C , 1980, Agents and Actions.

[29]  M. Bednar,et al.  Arachidonic acid monooxygenase and lipoxygenase activities in polymorphonuclear leukocytes. , 1987, Biochemical pharmacology.

[30]  Z. Werb,et al.  New functions for the matrix metalloproteinases in cancer progression , 2002, Nature Reviews Cancer.

[31]  A. Brash.  Arachidonic acid as a bioactive molecule. , 2001, The Journal of clinical investigation.

[32]  E. Lengyel,et al.  Stimulation of 92-kDa Gelatinase B Promoter Activity by ras Is Mitogen-activated Protein Kinase Kinase 1-independent and Requires Multiple Transcription Factor Binding Sites Including Closely Spaced PEA3/ets and AP-1 Sequences (*) , 1996, The Journal of Biological Chemistry.

[33]  C. Funk,et al.  The 5-lipoxygenase/leukotriene pathway in preclinical models of cardiovascular disease. , 2010, Cardiovascular research.

[34]  J. Uhm,et al.  Interferon β‐1b decreases the migration of T lymphocytes in vitro: Effects on matrix metalloproteinase‐9 , 1996 .

[35]  M. Yasuno,et al.  Expression of 5-lipoxygenase in human colorectal cancer. , 2006, World journal of gastroenterology.

[36]  F. Marks,et al.  A causal relationship between unscheduled eicosanoid signaling and tumor development: cancer chemoprevention by inhibitors of arachidonic acid metabolism. , 2000, Toxicology.

[37]  J. Palazzo,et al.  Pathologic features of Hashimoto's-associated papillary thyroid carcinomas. , 2001, Human pathology.

[38]  Takao Shimizu,et al.  Nuclear-localization-signal-dependent and nuclear-export-signal-dependent mechanisms determine the localization of 5-lipoxygenase. , 2002, The Biochemical journal.

[39]  M. Santoro,et al.  Description of a human papillary thyroid carcinoma cell line. Morphologic study and expression of tumoral markers , 1994, Cancer.

[40]  M. Goldyne,et al.  Arachidonic acid metabolism among human mononuclear leukocytes. Lipoxygenase-related pathways. , 1984, The Journal of biological chemistry.