title: Multiple splice variants of lactate dehydrogenase C selectively expressed in human cancer.
abstract: We applied a combined data mining and experimental validation Approach for the discovery of germ cell-specific genes aberrantly expressed in cancer. Six of 21 genes with confirmed germ cell specificity were detected in tumors, indicating that ectopic activation of testis-specific genes in cancer is a frequent phenomenon. Most surprisingly one of the genes represented lactate dehydrogenase C (LDHC), the germ cell-specific member of the lactate dehydrogenase family. LDHC escapes from transcriptional repression, resulting in significant expression levels in virtually all tumor types tested. Moreover, we discovered aberrant splicing of LDHC restricted to cancer cells, resulting in four novel tumor-specific variants displaying structural alterations of the catalytic domain. Expression of LDHC in tumors is neither mediated by gene promotor demethylation, as previously described for other germ cell-specific genes activated in cancer, nor induced by hypoxia as demonstrated for enzymes of the glycolytic pathway. LDHC represents the first lactate dehydrogenase isoform with restriction to tumor cells. In contrast to other LDH isoenzymes, LDHC has a preference for lactate as a substrate. Thus LDHC activation in cancer may provide a metabolic rescue pathway in tumor cells by exploiting lactate for ATP delivery.
authors.affiliation: Department of Internal Medicine, University Mainz, 55131 Mainz, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Koslowski
authors.forename: Ozlem
authors.initials: O
authors.lastname: Türeci
authors.forename: Carolin
authors.initials: C
authors.lastname: Bell
authors.forename: Patricia
authors.initials: P
authors.lastname: Krause
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Joachim
authors.initials: J
authors.lastname: Brunner
authors.forename: Gerhard
authors.initials: G
authors.lastname: Seitz
authors.forename: Frank Oliver
authors.initials: FO
authors.lastname: Nestle
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
mesh_terms: D017398:Alternative Splicing; D030561:Databases, Nucleic Acid; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics*; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013736:Testicular Neoplasms / Q000201:enzymology / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; C409673:lactate dehydrogenase C4