LOX Expression and Functional Analysis in Astrocytomas and Impact of IDH1 Mutation
Citações na Scopus
44
Tipo de produção
article
Data de publicação
2015
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PUBLIC LIBRARY SCIENCE
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PLOS ONE, v.10, n.3, article ID e0119781, 18p, 2015
Resumo
Lysyl oxidase (LOX) is involved in vital biological processes such as cell motility, cell signaling and gene regulation. Deregulation of this protein can contribute to tumor formation and progression. Although it is known that LOX is involved in invasion, proliferation and tumor migration in other types of tumors, studies of LOX in astrocytomas of different grades are scarce. The purpose of our study was to characterize LOX, BMP1 and HIF1A expression by real-time PCR in astrocytomas with WHO grades I to IV compared to non-neoplastic brain tissue. IDH1 mutational status was determined by PCR and sequencing. LOX protein expression was also analyzed by immunohistochemistry. LOX functional analyses were performed using siRNA knockdown and the specific inhibitor BAPN in two glioblastoma cell lines. The expression levels of LOX, BMP1 and HIF1A were correlated and analyzed according to IDH1 mutation status and to the clinical end-point of overall survival of glioblastoma patients. The results demonstrate that increased expression and activity of LOX, BMP1 and HIF1A were positively correlated with the malignant grade of astrocytomas. LOX protein expression also increased according to the degree of malignancy, with localization in the cytoplasm and nucleus and staining observed in endothelial cells. Glioblastoma with a mutation in IDH1 expressed lower levels of LOX in the nucleus, and IDH1-mutated cases showed lower LOX expression levels when compared to wild-type IDH1 cases. LOX knockdown and inhibition by BAPN in U87MG and A172 cell lines affected migration, invasion and soft agar colony formation. Taken together, these results corroborate the role of LOX in the migration, invasion and angiogenesis of astrocytomas. Furthermore, LOX expression is influenced by IDH1 mutational status. This work provides new insights for researchers aiming to design targeted therapies to control astrocytomas.
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Referências
- Abourbih DA, 2010, MELANOMA RES, V20, P97, DOI 10.1097/CMR.0b013e328336edfe
- Albinger-Hegyi A, 2010, INT J CANCER, V126, P2653, DOI 10.1002/ijc.24948
- AREM AJ, 1975, SURG FORUM, V26, P67
- Baker AM, 2013, CANCER RES, V73, P583, DOI 10.1158/0008-5472.CAN-12-2447
- Baker AM, 2011, J NATL CANCER I, V103, P407, DOI 10.1093/jnci/djq569
- Balss J, 2008, ACTA NEUROPATHOL, V116, P597, DOI 10.1007/s00401-008-0455-2
- Basuroy S, 2010, AM J PHYSIOL-GASTR L, V299, pG186, DOI 10.1152/ajpgi.00368.2009
- Bleeker FE, 2009, HUM MUTAT, V1, P7
- BOND JS, 1995, PROTEIN SCI, V4, P1247
- Bondareva A, 2009, PLOS ONE, V4, DOI 10.1371/journal.pone.0005620
- Carvalho PO, 2014, INT J BIOL MARKER, V29, pE120, DOI 10.5301/JBM.5000045
- Chen LC, 2012, BREAST CANCER RES TR, V134, P989, DOI 10.1007/s10549-012-1986-8
- Chesnelong C, 2013, NEURO-ONCOLOGY, V16, P686, DOI [10.1093/ neuonc/ not243, DOI 10.1093/NEU0NC/N0T243]
- Cox TR, 2011, DIS MODEL MECH, V4, P165, DOI 10.1242/dmm.004077
- Csiszar K, 2001, PROG NUCLEIC ACID RE, V70, P1, DOI 10.1016/S0079-6603(01)70012-8
- Dong YY, 2014, BIOCHEM BIOPH RES CO, V444, P427, DOI 10.1016/j.bbrc.2014.01.079
- El-Osta A, 2000, GENE EXPRESSION, V9, P63
- Erler JT, 2006, NATURE, V440, P1222, DOI 10.1038/nature04695
- Erler JT, 2009, CLIN EXP METASTAS, V26, P35, DOI 10.1007/s10585-008-9209-8
- Ge Gaoxiang, 2006, Birth Defects Research, V78, P47, DOI 10.1002/bdrc.20060
- Gravendeel LAM, 2010, HUM MUTAT, V31, pE1186, DOI 10.1002/humu.21201
- Ichimura K, 2009, NEURO-ONCOLOGY, V11, P341, DOI 10.1215/15228517-2009-025
- Ji F, 2013, INT J ONCOL, V42, P1578, DOI 10.3892/ijo.2013.1878
- KAGAN HM, 1991, AM J RESP CELL MOL, V5, P206
- Kagan HM, 2003, J CELL BIOCHEM, V88, P660, DOI 10.1002/jcb.10413
- Kaneda A, 2004, CANCER RES, V64, P6410, DOI 10.1158/0008-5472.CAN-04-1543
- Kessler E, 1996, SCIENCE, V271, P360, DOI 10.1126/science.271.5247.360
- Kirschmann DA, 2002, CANCER RES, V62, P4478
- Laczko R, 2007, NEUROPATH APPL NEURO, V33, P631, DOI 10.1111/j.1365-2990.2007.00858.x
- Lai A, 2011, J CLIN ONCOL, V29, P4482, DOI 10.1200/JCO.2010.33.8715
- Lazarus HM, 1995, MATRIX BIOL, V14, P727, DOI 10.1016/S0945-053X(05)80015-0
- Lee K, 2006, CHEM RES TOXICOL, V19, P1284, DOI 10.1021/tx060068d
- Levental KR, 2009, CELL, V139, P891, DOI 10.1016/j.cell.2009.10.027
- Li PA, 2004, MOL BRAIN RES, V120, P115, DOI 10.1016/j.molbrainres.2003.10.013
- Li WD, 1997, P NATL ACAD SCI USA, V94, P12817, DOI 10.1073/pnas.94.24.12817
- Louis DN, 2007, ACTA NEUROPATHOL, V114, P97, DOI 10.1007/s00401-007-0243-4
- Mammoto T, 2013, AM J PATHOL, V183, P1293, DOI 10.1016/j.ajpath.2013.06.026
- Maruhashi T, 2010, J BIOL CHEM, V285, P13294, DOI 10.1074/jbc.M109.088864
- Mustafa D, 2013, J NEUROPATHOL EXP NE, V7, P1171
- Nellaiappan K, 2000, J CELL BIOCHEM, V79, P576, DOI 10.1002/1097-4644(20001215)79:4<576::AID-JCB60>3.0.CO;2-A
- Nishioka T, 2012, CELL STRUCT FUNCT, V37, P75
- Nobusawa S, 2009, CLIN CANCER RES, V15, P6002, DOI 10.1158/1078-0432.CCR-09-0715
- Noushmehr H, 2010, CANCER CELL, V17, P510, DOI 10.1016/j.ccr.2010.03.017
- Ohgaki H, 2013, CLIN CANCER RES, V19, P764, DOI 10.1158/1078-0432.CCR-12-3002
- Ohgaki H, 2011, BRAIN TUMOR PATHOL, V28, P177, DOI 10.1007/s10014-011-0029-1
- Osawa T, 2013, BRIT J CANCER, V109, P2237, DOI 10.1038/bjc.2013.535
- Parsons DW, 2008, SCIENCE, V321, P1807, DOI 10.1126/science.1164382
- Pez F, 2011, CANCER RES, V71, P1647, DOI 10.1158/0008-5472.CAN-10-1516
- Ping W, 2013, ASIAN PAC J CANCER P, V14, P3613, DOI 10.7314/APJCP.2013.14.6.3613
- Saad FA, 2010, BIOCHEM BIOPH RES CO, V396, P944, DOI 10.1016/j.bbrc.2010.05.028
- Sakai M, 2009, ANN SURG ONCOL, V16, P2494, DOI 10.1245/s10434-009-0559-5
- Schietke R, 2010, J BIOL CHEM, V285, P6658, DOI 10.1074/jbc.M109.042424
- Schmittgen TD, 2008, NAT PROTOC, V3, P1101, DOI 10.1038/nprot.2008.73
- SHERIDAN PJ, 1979, EXP MOL PATHOL, V30, P315, DOI 10.1016/0014-4800(79)90063-7
- Shih YH, 2013, HEAD NECK-J SCI SPEC, V35, P250, DOI 10.1002/hed.22959
- Smith-Mungo LI, 1998, MATRIX BIOL, V16, P387, DOI 10.1016/S0945-053X(98)90012-9
- Sterchi EE, 2008, MOL ASPECTS MED, V29, P309, DOI 10.1016/j.mam.2008.08.002
- Stewart GD, 2008, ONCOL REP, V20, P1561, DOI 10.3892/or_00000180
- Uno M, 2005, CANCER LETT, V224, P321, DOI 10.1016/j.canlet.2004.10.022
- Uno M, 2011, CLINICS, V66, P163, DOI 10.1590/S1807-59322011000100028
- Watanabe T, 2009, AM J PATHOL, V174, P1149, DOI 10.2353/ajpath.2009.080958
- Weller M, 2011, GLIA, V59, P1200, DOI 10.1002/glia.21130
- Wiel C, 2013, CELL DEATH DIS, V4, DOI 10.1038/cddis.2013.382
- Yan H, 2009, NEW ENGL J MED, V360, P765, DOI 10.1056/NEJMoa0808710
- Yang XX, 2013, ONCOL REP, V29, P541, DOI 10.3892/or.2012.2146