title: Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer.
abstract: Lactate dehydrogenase 5 (LDH5) is one of the five LDH isoenzymes and, apparently, the most important for promoting anaerobic glycolysis. LDH5 is transcriptionally regulated by the hypoxia inducible factors (HIF) 1alpha and 2alpha. In this study, the possible aggressive advantages that colorectal tumours may gain from a high LDH5 content was investigated. To this end, 75 colorectal adenocarcinomas were studied immunohistochemically for the expression of LDH5, and the results were related to tumor differentiation, lymph node and distant metastases, the expression of HIF1alpha and HIF2alpha, vascular density (VD) and vascular endothelial growth factor (VEGF). A high LDH5 content was noted in 51 of 75 (68%) colorectal adenocarcinomas. The reactivity was nuclear and/or cytoplasmic. Nuclear LDH5 reactivity was correlated with lymph node involvement and distant metastases. There was a direct association between LDH5 up-regulation and HIF1alpha and HIF2alpha accumulation. HIF1alpha was linked with VEGF, VD and also with extramural invasion, nodal and distant metastases. It is concluded that a high LDH5 content in tumor cells is directly related to an up-regulated HIF pathway and is linked with an aggressive phenotype in colorectal adenocarcinomas.
authors.affiliation: Department of Radiotherapy/Oncology, Democritus University of Thrace Medical School, 68100 Alexandroupolis, Greece. targ@her.forthnet.gr
authors.forename: Michael I
authors.initials: MI
authors.lastname: Koukourakis
authors.forename: Alexandra
authors.initials: A
authors.lastname: Giatromanolaki
authors.forename: Costantinos
authors.initials: C
authors.lastname: Simopoulos
authors.forename: Alexandros
authors.initials: A
authors.lastname: Polychronidis
authors.forename: Efthimios
authors.initials: E
authors.lastname: Sivridis
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D051792:Basic Helix-Loop-Helix Proteins; D015687:Cell Hypoxia; D002467:Cell Nucleus / Q000201:enzymology; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D003593:Cytoplasm / Q000201:enzymology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000032:analysis / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D008207:Lymphatic Metastasis; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000201:enzymology; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human