Absence of MGST1 mRNA and protein expression in human neuroblastoma cell lines and primary tissue.
A recent study identified a haplotype on a small region of chromosome 12, between markers D12S1725 and D12S1596, shared by all patients with familial neuroblastoma (NB). We previously localized the human MGST1 gene, whose gene product protects against oxidative stress, to this very same chromosomal region (12p112.1-p13.33). Owing to the chromosomal location of MGST1; its roles in tumorigenesis, drug resistance, and oxidative stress; and the known sensitivity of NB cell lines to oxidative stress, we considered a role for MGST1 in NB development. Surprisingly there was no detectable MGST1 mRNA or protein in either NB cell lines or NB primary tumor tissue, although all other human tissues, cell lines, and primary tumor tissue examined to date express MGST1 at high levels. The mechanism behind the failure of NB cells and tissue to express MGST1 mRNA is unknown and involves the failure of MGST1 pre-mRNA expression, but does not involve chromosomal rearrangement or nucleotide variation in the promoter, exons, or 3' untranslated region of MGST1. MGST1 provides significant protection against oxidative stress and constitutes 4 to 6% of all protein in the outer membrane of the mitochondria. As NB cells are extremely sensitive to oxidative stress, and often used as a model system to investigate mitochondrial response to endogenous and exogenous stress, these findings may be due to the lack of expression MGST1 protein in NB. The significance of this finding to the development of neuroblastoma (familial or otherwise), however, is unknown and may even be incidental. Although our studies provide a molecular basis for previous work on the sensitivity of NB cells to oxidative stress, and possibly marked variations in NB mitochondrial homeostasis, they also imply that the results of these earlier studies using NB cells are not transferable to other tumor and cell types that express MGST1 at high concentrations.
Department of Pathology, University of California at San Diego, La Jolla, CA 92039, USA. Electronic address: mkelner@ucsd.edu.
Michael J
MJ
Kelner
Department of Pediatrics, University of California at San Diego, La Jolla, CA 92039, USA.
Mitchell B
MB
Diccianni
Department of Pediatrics, University of California at San Diego, La Jolla, CA 92039, USA; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
Alice L
AL
Yu
Department of Pathology, University of California at San Diego, La Jolla, CA 92039, USA.
Mary R
MR
Rutherford
Department of Pathology, University of California at San Diego, La Jolla, CA 92039, USA.
Leita A
LA
Estes
Institute of Environmental Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden.
Ralf
R
Morgenstern
D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000096:biosynthesis*; D006801:Humans; D008928:Mitochondria / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis*
D012333:RNA, Messenger; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase
Free radicals; MAPEG; MGST1; MGST2; MGST3; Microsomal glutathione transferase; Neuroblastoma; Oxidative stress