Department of Pathology, University of California at San Diego, La Jolla, CA 92039, USA.
Department of Pediatrics, University of California at San Diego, La Jolla, CA 92039, USA.
Free Radic Biol Med. 2014 Apr;69:167-71. doi: 10.1016/j.freeradbiomed.2014.01.021. Epub 2014 Jan 29.
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.
最近的一项研究确定了一个小染色体 12 区域的单倍型，该区域位于标记物 D12S1725 和 D12S1596 之间，所有家族性神经母细胞瘤 (NB) 患者都具有该区域的单倍型。我们之前将人类 MGST1 基因定位到了这个相同的染色体区域（12p112.1-p13.33），该基因的产物可以抵抗氧化应激。由于 MGST1 的染色体位置；其在肿瘤发生、耐药性和氧化应激中的作用；以及已知 NB 细胞系对氧化应激的敏感性，我们认为 MGST1 在 NB 发育中起作用。令人惊讶的是，无论是在 NB 细胞系还是 NB 原发性肿瘤组织中，都检测不到可检测的 MGST1 mRNA 或蛋白质，尽管迄今为止检查的所有其他人类组织、细胞系和原发性肿瘤组织都高度表达 MGST1。NB 细胞和组织未能表达 MGST1 mRNA 的机制尚不清楚，涉及 MGST1 前体 mRNA 表达的失败，但不涉及 MGST1 启动子、外显子或 3'非翻译区的染色体重排或核苷酸变异。MGST1 为氧化应激提供了显著的保护作用，占线粒体外膜中所有蛋白质的 4%至 6%。由于 NB 细胞对氧化应激极其敏感，并且经常被用作研究线粒体对内源性和外源性应激反应的模型系统，因此这些发现可能是由于 NB 中缺乏 MGST1 蛋白的表达。然而，这一发现对神经母细胞瘤（家族性或其他类型）的发展的意义尚不清楚，甚至可能是偶然的。尽管我们的研究为之前关于 NB 细胞对氧化应激敏感性的工作以及可能的 NB 线粒体动态平衡的显著变化提供了分子基础，但它们也意味着这些使用 NB 细胞的早期研究的结果不能转移到其他高浓度表达 MGST1 的肿瘤和细胞类型。
