Increased expression of LDHA mRNA and increased cytoplasmic to nuclear ratio of LDHA protein predicts poor prognosis in neuroblastoma
Barth, Thomas F. E.
InstitutionsUniversitätsklinikum Ulm, Klinik für Kinder- und Jugendmedizin
Universitätsklinikum Ulm, Institut für Pathologie
Neuroblastoma (NB) is the most common extracranial tumor diagnosed during infancy and childhood. Despite forced research efforts survival of children with high risk disease is still less than 40%. Unfavorable NB are characterized by genetic aberrations. The most common is amplification of MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog). Revealing metabolism in cancer cells has been the aim of exhaustive research over the past years. Aerobic glycolysis or the Warburg effect, first described in the 1920’s, has been identified as major metabolic pathway in solid tumors. Diverse oncogenes and HIF1-α (Hypoxia-inducible factor 1 α) are master regulators of the Warburg pathway by inducing its key molecules GLUT1 (glucose transporter 1), PDK1 (pyruvate dehydrogenase kinase isoenzyme 1), PKM2 (pyruvate kinase type M2) and LDHA (lactate dehydrogenase A) directly or in cooperation. In this study we provide an insight into the role of the Warburg effect in NB. By investigating the Warburg enzymes in a sample of different MYCN-amplified and non-amplified NB cell lines, we showed that the cells have a glycolytic phenotype. Enzymes were expressed with diverse intensity. LDHA was shown to be apparently dispensable for the Warburg effect in neuroblastoma cell lines, as aerobic glycolysis was maintained in vitro and in vivo in neuroblastoma cells, lacking LDHA. In this work we could not draw a direct correlation between MYCN status and the expression levels of the different Warburg molecules. In comparison to MYC (v-myc avian myelocytomatosis viral oncogene), MYCN is maybe associated but apparently does not directly influence expression levels of glycolytic enzymes. Immunohistochemical examination of LDHA expression in primary NB clearly indicated a relation of the common NB risk factors for bad prognosis (amplified MYCN, advanced tumor stage, worse differentiation status, high risk group and older age) and the intensity of LDHA expression. LDHA expression quantity and compartmental localization offers a new indicator for neuroblastoma aggressiveness.
Subject HeadingsNeuroblastom [GND]