Over-expression of lysyl oxidase is associated with poor prognosis and response to therapy of patients with lower grade gliomas

S.-P. Huang, J. Chiou, Y.-H. Jan, T.-C. Lai, Y.-L. Yu, M. Hsiao, Y.-F. Lin

Research output: Contribution to journalArticle

Abstract

Lower grade gliomas (LGGs) have highly diverse clinical phenotypes. The histological grade and type are insufficient to accurately predict the clinical outcomes of patients with LGGs. Therefore, identification of biomarkers that can facilitate the prediction of clinical outcomes in LGGs is urgently needed. Gene expression of LOX has been identified as a biomarker for various cancers. However, the clinical significance of LOX expression in LGGs has not been investigated. In this study, we analyzed the glioma RNA-seq dataset from TCGA (The Cancer Genome atlas) and identified lysyl oxidase (LOX) as a potential biomarker for LGGs. Kaplan-Meier survival analysis revealed that high LOX expression is associated with worse overall survival and recurrence free survival in LGG patients. Besides, high LOX expression is associated with poor response to primary therapy, follow-up treatment, targeted molecular therapy, and radiation therapy. Univariate and multivariate Cox regression analyses further confirmed LOX expression as an independent prognostic factor for LGG patients. Finally, we observed that LOX expression is significantly correlated with EMT (epithelial to mesenchymal transition) and IDH1 status in LGGs. In conclusion, our analyses suggest that LOX expression is a potential biomarker for prognosis and therapeutic response in LGGs. © 2018
Original languageEnglish
Pages (from-to)619-627
Number of pages9
JournalBiochemical and Biophysical Research Communications
Volume501
Issue number3
DOIs
Publication statusPublished - 2018

Fingerprint

Protein-Lysine 6-Oxidase
Glioma
Biomarkers
Therapeutics
Molecular Targeted Therapy
Radiotherapy
Tumor Biomarkers
Gene expression
Epithelial-Mesenchymal Transition
Survival
Atlases
Kaplan-Meier Estimate
Survival Analysis
Genes
RNA
Regression Analysis

Keywords

  • Biomarker
  • EMT
  • IDH1
  • Lower grade gliomas (LGGs)
  • Lysyl oxidase (LOX)
  • TCGA
  • bevacizumab
  • isocitrate dehydrogenase 1
  • protein lysine 6 oxidase
  • adult
  • Article
  • cancer prognosis
  • cancer radiotherapy
  • cohort analysis
  • controlled study
  • epithelial mesenchymal transition
  • female
  • follow up
  • gene expression
  • gene mutation
  • genetic association
  • glioma
  • human
  • IDH1 gene
  • LOX gene
  • major clinical study
  • male
  • molecularly targeted therapy
  • overall survival
  • priority journal
  • recurrence free survival
  • RNA sequence
  • treatment response

Cite this

Over-expression of lysyl oxidase is associated with poor prognosis and response to therapy of patients with lower grade gliomas. / Huang, S.-P.; Chiou, J.; Jan, Y.-H.; Lai, T.-C.; Yu, Y.-L.; Hsiao, M.; Lin, Y.-F.

In: Biochemical and Biophysical Research Communications, Vol. 501, No. 3, 2018, p. 619-627.

Research output: Contribution to journalArticle

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title = "Over-expression of lysyl oxidase is associated with poor prognosis and response to therapy of patients with lower grade gliomas",
abstract = "Lower grade gliomas (LGGs) have highly diverse clinical phenotypes. The histological grade and type are insufficient to accurately predict the clinical outcomes of patients with LGGs. Therefore, identification of biomarkers that can facilitate the prediction of clinical outcomes in LGGs is urgently needed. Gene expression of LOX has been identified as a biomarker for various cancers. However, the clinical significance of LOX expression in LGGs has not been investigated. In this study, we analyzed the glioma RNA-seq dataset from TCGA (The Cancer Genome atlas) and identified lysyl oxidase (LOX) as a potential biomarker for LGGs. Kaplan-Meier survival analysis revealed that high LOX expression is associated with worse overall survival and recurrence free survival in LGG patients. Besides, high LOX expression is associated with poor response to primary therapy, follow-up treatment, targeted molecular therapy, and radiation therapy. Univariate and multivariate Cox regression analyses further confirmed LOX expression as an independent prognostic factor for LGG patients. Finally, we observed that LOX expression is significantly correlated with EMT (epithelial to mesenchymal transition) and IDH1 status in LGGs. In conclusion, our analyses suggest that LOX expression is a potential biomarker for prognosis and therapeutic response in LGGs. {\circledC} 2018",
keywords = "Biomarker, EMT, IDH1, Lower grade gliomas (LGGs), Lysyl oxidase (LOX), TCGA, bevacizumab, isocitrate dehydrogenase 1, protein lysine 6 oxidase, adult, Article, cancer prognosis, cancer radiotherapy, cohort analysis, controlled study, epithelial mesenchymal transition, female, follow up, gene expression, gene mutation, genetic association, glioma, human, IDH1 gene, LOX gene, major clinical study, male, molecularly targeted therapy, overall survival, priority journal, recurrence free survival, RNA sequence, treatment response",
author = "S.-P. Huang and J. Chiou and Y.-H. Jan and T.-C. Lai and Y.-L. Yu and M. Hsiao and Y.-F. Lin",
note = "Export Date: 27 October 2018 CODEN: BBRCA Correspondence Address: Lin, Y.-F.; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taiwan; email: d001089012@tmu.edu.tw Chemicals/CAS: bevacizumab, 216974-75-3, 1438851-35-4; protein lysine 6 oxidase, 99676-44-5 References: Stupp, R., Mason, W.P., van den Bent, M.J., Weller, M., Fisher, B., Taphoorn, M.J., Belanger, K., Mirimanoff, R.O., R. European organisation for, T. Treatment of cancer brain, G. Radiotherapy, G. National cancer institute of Canada clinical trials, radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma (2005) N. Engl. J. Med., 352, pp. 987-996; Louis, D.N., Ohgaki, H., Wiestler, O.D., Cavenee, W.K., Burger, P.C., Jouvet, A., Scheithauer, B.W., Kleihues, P., The 2007 WHO classification of tumours of the central nervous system (2007) Acta Neuropathol., 114, pp. 97-109; Ostrom, Q.T., Gittleman, H., Fulop, J., Liu, M., Blanda, R., Kromer, C., Wolinsky, Y., Barnholtz-Sloan, J.S., CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012 (2015) Neuro Oncol., 17. , iv1-iv62; Bourne, T.D., Schiff, D., Update on molecular findings, management and outcome in low-grade gliomas (2010) Nat. Rev. Neurol., 6, pp. 695-701; Mahaley, M.S., Jr., Mettlin, C., Natarajan, N., Laws, E.R., Jr., Peace, B.B., National survey of patterns of care for brain-tumor patients (1989) J. Neurosurg., 71, pp. 826-836; Kalinina, J., Peng, J., Ritchie, J.C., Van Meir, E.G., Proteomics of gliomas: initial biomarker discovery and evolution of technology (2011) Neuro Oncol., 13, pp. 926-942; Denko, N.C., Fontana, L.A., Hudson, K.M., Sutphin, P.D., Raychaudhuri, S., Altman, R., Giaccia, A.J., Investigating hypoxic tumor physiology through gene expression patterns (2003) Oncogene, 22, pp. 5907-5914; Erler, J.T., Bennewith, K.L., Nicolau, M., Dornhofer, N., Kong, C., Le, Q.T., Chi, J.T., Giaccia, A.J., Lysyl oxidase is essential for hypoxia-induced metastasis (2006) Nature, 440, pp. 1222-1226; da Silva, R., Uno, M., Marie, S.K., Oba-Shinjo, S.M., LOX expression and functional analysis in astrocytomas and impact of IDH1 mutation (2015) PLoS One, 10; Barker, H.E., Cox, T.R., Erler, J.T., The rationale for targeting the LOX family in cancer (2012) Nat. Rev. Canc., 12, pp. 540-552; Albinger-Hegyi, A., Stoeckli, S.J., Schmid, S., Storz, M., Iotzova, G., Probst-Hensch, N.M., Rehrauer, H., Hegyi, I., Lysyl oxidase expression is an independent marker of prognosis and a predictor of lymph node metastasis in oral and oropharyngeal squamous cell carcinoma (OSCC) (2010) Int. J. Canc., 126, pp. 2653-2662; Wilgus, M.L., Borczuk, A.C., Stoopler, M., Ginsburg, M., Gorenstein, L., Sonett, J.R., Powell, C.A., Lysyl oxidase: a lung adenocarcinoma biomarker of invasion and survival (2011) Cancer, 117, pp. 2186-2191; Ross, D.T., Scherf, U., Eisen, M.B., Perou, C.M., Rees, C., Spellman, P., Iyer, V., Brown, P.O., Systematic variation in gene expression patterns in human cancer cell lines (2000) Nat. Genet., 24, pp. 227-235; Freije, W.A., Castro-Vargas, F.E., Fang, Z., Horvath, S., Cloughesy, T., Liau, L.M., Mischel, P.S., Nelson, S.F., Gene expression profiling of gliomas strongly predicts survival (2004) Canc. Res., 64, pp. 6503-6510; Laczko, R., Szauter, K.M., Jansen, M.K., Hollosi, P., Muranyi, M., Molnar, J., Fong, K.S., Csiszar, K., Active lysyl oxidase (LOX) correlates with focal adhesion kinase (FAK)/paxillin activation and migration in invasive astrocytes (2007) Neuropathol. Appl. Neurobiol., 33, pp. 631-643; Leighton, C., Fisher, B., Bauman, G., Depiero, S., Stitt, L., MacDonald, D., Cairncross, G., Supratentorial low-grade glioma in adults: an analysis of prognostic factors and timing of radiation (1997) J. Clin. Oncol., 15, pp. 1294-1301; Gill, S., Sargent, D., End points for adjuvant therapy trials: has the time come to accept disease-free survival as a surrogate end point for overall survival? (2006) Oncol., 11, pp. 624-629; Cox, T.R., Rumney, R.M., Schoof, E.M., Perryman, L., Hoye, A.M., Agrawal, A., Bird, D., Erler, J.T., The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase (2015) Nature, 522, pp. 106-110; Kasashima, H., Yashiro, M., Kinoshita, H., Fukuoka, T., Morisaki, T., Masuda, G., Sakurai, K., Hirakawa, K., Lysyl oxidase is associated with the epithelial-mesenchymal transition of gastric cancer cells in hypoxia (2016) Gastric Cancer, 19, pp. 431-442; Parsons, D.W., Jones, S., Zhang, X., Lin, J.C., Leary, R.J., Angenendt, P., Mankoo, P., Kinzler, K.W., An integrated genomic analysis of human glioblastoma multiforme (2008) Science, 321, pp. 1807-1812; Yan, H., Parsons, D.W., Jin, G., McLendon, R., Rasheed, B.A., Yuan, W., Kos, I., Bigner, D.D., IDH1 and IDH2 mutations in gliomas (2009) N. Engl. J. Med., 360, pp. 765-773",
year = "2018",
doi = "10.1016/j.bbrc.2018.04.228",
language = "English",
volume = "501",
pages = "619--627",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Elsevier B.V.",
number = "3",

}

TY - JOUR

T1 - Over-expression of lysyl oxidase is associated with poor prognosis and response to therapy of patients with lower grade gliomas

AU - Huang, S.-P.

AU - Chiou, J.

AU - Jan, Y.-H.

AU - Lai, T.-C.

AU - Yu, Y.-L.

AU - Hsiao, M.

AU - Lin, Y.-F.

N1 - Export Date: 27 October 2018 CODEN: BBRCA Correspondence Address: Lin, Y.-F.; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taiwan; email: d001089012@tmu.edu.tw Chemicals/CAS: bevacizumab, 216974-75-3, 1438851-35-4; protein lysine 6 oxidase, 99676-44-5 References: Stupp, R., Mason, W.P., van den Bent, M.J., Weller, M., Fisher, B., Taphoorn, M.J., Belanger, K., Mirimanoff, R.O., R. European organisation for, T. Treatment of cancer brain, G. Radiotherapy, G. National cancer institute of Canada clinical trials, radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma (2005) N. Engl. J. Med., 352, pp. 987-996; Louis, D.N., Ohgaki, H., Wiestler, O.D., Cavenee, W.K., Burger, P.C., Jouvet, A., Scheithauer, B.W., Kleihues, P., The 2007 WHO classification of tumours of the central nervous system (2007) Acta Neuropathol., 114, pp. 97-109; Ostrom, Q.T., Gittleman, H., Fulop, J., Liu, M., Blanda, R., Kromer, C., Wolinsky, Y., Barnholtz-Sloan, J.S., CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012 (2015) Neuro Oncol., 17. , iv1-iv62; Bourne, T.D., Schiff, D., Update on molecular findings, management and outcome in low-grade gliomas (2010) Nat. Rev. Neurol., 6, pp. 695-701; Mahaley, M.S., Jr., Mettlin, C., Natarajan, N., Laws, E.R., Jr., Peace, B.B., National survey of patterns of care for brain-tumor patients (1989) J. Neurosurg., 71, pp. 826-836; Kalinina, J., Peng, J., Ritchie, J.C., Van Meir, E.G., Proteomics of gliomas: initial biomarker discovery and evolution of technology (2011) Neuro Oncol., 13, pp. 926-942; Denko, N.C., Fontana, L.A., Hudson, K.M., Sutphin, P.D., Raychaudhuri, S., Altman, R., Giaccia, A.J., Investigating hypoxic tumor physiology through gene expression patterns (2003) Oncogene, 22, pp. 5907-5914; Erler, J.T., Bennewith, K.L., Nicolau, M., Dornhofer, N., Kong, C., Le, Q.T., Chi, J.T., Giaccia, A.J., Lysyl oxidase is essential for hypoxia-induced metastasis (2006) Nature, 440, pp. 1222-1226; da Silva, R., Uno, M., Marie, S.K., Oba-Shinjo, S.M., LOX expression and functional analysis in astrocytomas and impact of IDH1 mutation (2015) PLoS One, 10; Barker, H.E., Cox, T.R., Erler, J.T., The rationale for targeting the LOX family in cancer (2012) Nat. Rev. Canc., 12, pp. 540-552; Albinger-Hegyi, A., Stoeckli, S.J., Schmid, S., Storz, M., Iotzova, G., Probst-Hensch, N.M., Rehrauer, H., Hegyi, I., Lysyl oxidase expression is an independent marker of prognosis and a predictor of lymph node metastasis in oral and oropharyngeal squamous cell carcinoma (OSCC) (2010) Int. J. Canc., 126, pp. 2653-2662; Wilgus, M.L., Borczuk, A.C., Stoopler, M., Ginsburg, M., Gorenstein, L., Sonett, J.R., Powell, C.A., Lysyl oxidase: a lung adenocarcinoma biomarker of invasion and survival (2011) Cancer, 117, pp. 2186-2191; Ross, D.T., Scherf, U., Eisen, M.B., Perou, C.M., Rees, C., Spellman, P., Iyer, V., Brown, P.O., Systematic variation in gene expression patterns in human cancer cell lines (2000) Nat. Genet., 24, pp. 227-235; Freije, W.A., Castro-Vargas, F.E., Fang, Z., Horvath, S., Cloughesy, T., Liau, L.M., Mischel, P.S., Nelson, S.F., Gene expression profiling of gliomas strongly predicts survival (2004) Canc. Res., 64, pp. 6503-6510; Laczko, R., Szauter, K.M., Jansen, M.K., Hollosi, P., Muranyi, M., Molnar, J., Fong, K.S., Csiszar, K., Active lysyl oxidase (LOX) correlates with focal adhesion kinase (FAK)/paxillin activation and migration in invasive astrocytes (2007) Neuropathol. Appl. Neurobiol., 33, pp. 631-643; Leighton, C., Fisher, B., Bauman, G., Depiero, S., Stitt, L., MacDonald, D., Cairncross, G., Supratentorial low-grade glioma in adults: an analysis of prognostic factors and timing of radiation (1997) J. Clin. Oncol., 15, pp. 1294-1301; Gill, S., Sargent, D., End points for adjuvant therapy trials: has the time come to accept disease-free survival as a surrogate end point for overall survival? (2006) Oncol., 11, pp. 624-629; Cox, T.R., Rumney, R.M., Schoof, E.M., Perryman, L., Hoye, A.M., Agrawal, A., Bird, D., Erler, J.T., The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase (2015) Nature, 522, pp. 106-110; Kasashima, H., Yashiro, M., Kinoshita, H., Fukuoka, T., Morisaki, T., Masuda, G., Sakurai, K., Hirakawa, K., Lysyl oxidase is associated with the epithelial-mesenchymal transition of gastric cancer cells in hypoxia (2016) Gastric Cancer, 19, pp. 431-442; Parsons, D.W., Jones, S., Zhang, X., Lin, J.C., Leary, R.J., Angenendt, P., Mankoo, P., Kinzler, K.W., An integrated genomic analysis of human glioblastoma multiforme (2008) Science, 321, pp. 1807-1812; Yan, H., Parsons, D.W., Jin, G., McLendon, R., Rasheed, B.A., Yuan, W., Kos, I., Bigner, D.D., IDH1 and IDH2 mutations in gliomas (2009) N. Engl. J. Med., 360, pp. 765-773

PY - 2018

Y1 - 2018

N2 - Lower grade gliomas (LGGs) have highly diverse clinical phenotypes. The histological grade and type are insufficient to accurately predict the clinical outcomes of patients with LGGs. Therefore, identification of biomarkers that can facilitate the prediction of clinical outcomes in LGGs is urgently needed. Gene expression of LOX has been identified as a biomarker for various cancers. However, the clinical significance of LOX expression in LGGs has not been investigated. In this study, we analyzed the glioma RNA-seq dataset from TCGA (The Cancer Genome atlas) and identified lysyl oxidase (LOX) as a potential biomarker for LGGs. Kaplan-Meier survival analysis revealed that high LOX expression is associated with worse overall survival and recurrence free survival in LGG patients. Besides, high LOX expression is associated with poor response to primary therapy, follow-up treatment, targeted molecular therapy, and radiation therapy. Univariate and multivariate Cox regression analyses further confirmed LOX expression as an independent prognostic factor for LGG patients. Finally, we observed that LOX expression is significantly correlated with EMT (epithelial to mesenchymal transition) and IDH1 status in LGGs. In conclusion, our analyses suggest that LOX expression is a potential biomarker for prognosis and therapeutic response in LGGs. © 2018

AB - Lower grade gliomas (LGGs) have highly diverse clinical phenotypes. The histological grade and type are insufficient to accurately predict the clinical outcomes of patients with LGGs. Therefore, identification of biomarkers that can facilitate the prediction of clinical outcomes in LGGs is urgently needed. Gene expression of LOX has been identified as a biomarker for various cancers. However, the clinical significance of LOX expression in LGGs has not been investigated. In this study, we analyzed the glioma RNA-seq dataset from TCGA (The Cancer Genome atlas) and identified lysyl oxidase (LOX) as a potential biomarker for LGGs. Kaplan-Meier survival analysis revealed that high LOX expression is associated with worse overall survival and recurrence free survival in LGG patients. Besides, high LOX expression is associated with poor response to primary therapy, follow-up treatment, targeted molecular therapy, and radiation therapy. Univariate and multivariate Cox regression analyses further confirmed LOX expression as an independent prognostic factor for LGG patients. Finally, we observed that LOX expression is significantly correlated with EMT (epithelial to mesenchymal transition) and IDH1 status in LGGs. In conclusion, our analyses suggest that LOX expression is a potential biomarker for prognosis and therapeutic response in LGGs. © 2018

KW - Biomarker

KW - EMT

KW - IDH1

KW - Lower grade gliomas (LGGs)

KW - Lysyl oxidase (LOX)

KW - TCGA

KW - bevacizumab

KW - isocitrate dehydrogenase 1

KW - protein lysine 6 oxidase

KW - adult

KW - Article

KW - cancer prognosis

KW - cancer radiotherapy

KW - cohort analysis

KW - controlled study

KW - epithelial mesenchymal transition

KW - female

KW - follow up

KW - gene expression

KW - gene mutation

KW - genetic association

KW - glioma

KW - human

KW - IDH1 gene

KW - LOX gene

KW - major clinical study

KW - male

KW - molecularly targeted therapy

KW - overall survival

KW - priority journal

KW - recurrence free survival

KW - RNA sequence

KW - treatment response

U2 - 10.1016/j.bbrc.2018.04.228

DO - 10.1016/j.bbrc.2018.04.228

M3 - Article

VL - 501

SP - 619

EP - 627

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 3

ER -