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首页> 外文期刊>Amyloid: the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis >Oligomeric TTR V30M aggregates compromise cell viability, erythropoietin gene expression and promoter activity in the human hepatoma cell line Hep3B
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Oligomeric TTR V30M aggregates compromise cell viability, erythropoietin gene expression and promoter activity in the human hepatoma cell line Hep3B

机译：寡聚TTR V30M聚集在人肝癌细胞系Hep3B中损害细胞活力，促红细胞生成素基因表达和启动子活性

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摘要

Familial amyloidotic polyneuropathy, ATTRV30M (p.TTRV50M) amyloidosis, is a neurodegenerative disease characterized by systemic extracellular amyloid deposition of a mutant transthyretin, TTR V30M. Anemia, with low erythropoietin (EPO) levels and spared kidney function, affects about 25% of symptomatic patients, suggesting a blockage of EPO-producing cells. Early non-fibrillar TTR aggregates are highly cytotoxic, inducing oxidative stress, the expression of apoptosis-related molecules and secretion of pro-inflammatory cytokines, factors capable of inhibiting EPO production. Low EPO levels in these patients are not related to renal amyloid deposition or the presence of circulating TTR V30M. However, the role of early non-fibrillar TTR aggregates remains unexplored. We used the EPO producing Hep3B human hepatoma cell line to study the effect of TTR oligomeric aggregates on EPO expression. Hep3B cells were incubated with soluble and oligomeric TTR V30M, and cell proliferation as well as caspase 3/7 activation was evaluated. Relative quantification of EPO mRNA transcripts was performed by real-time PCR. Significant reductions in cell viability (13 +/- 7.3%) and activation of caspases 3/7 were seen after 24 h in the presence of oligomeric TTR V30M. Also, EPO expression was significantly reduced (50 +/- 2.8%), in normoxic conditions. A reporter assay was constructed with a PCR fragment of the EPO promoter linked to the luciferase gene to evaluate the role of transcription factors targeting the promoter. A significant reduction of EPO promoter activity (53 +/- 6.5%) was observed in transfected cells exposed to TTR oligomers. Our results show that oligomeric TTR V30M reduces EPO expression, at least in part through inhibition of promoter activity.
机译：家族性淀粉样变性多发性神经病，ATTRV30M（p.TTRV50M）淀粉样变性病，是一种神经退行性疾病，其特征是突变型甲状腺素TTR V30M的全身细胞外淀粉样蛋白沉积。贫血，促红细胞生成素（EPO）含量低且肾脏功能不佳，影响约25％的有症状患者，提示EPO产生细胞受阻。早期的非原纤维TTR聚集体具有高度的细胞毒性，可诱导氧化应激，凋亡相关分子的表达和促炎性细胞因子的分泌，这些都是能够抑制EPO产生的因子。这些患者中的低EPO水平与肾淀粉样蛋白沉积或循环中TTR V30M的存在无关。但是，早期非原纤维TTR聚集体的作用仍待探索。我们使用产生EPO的Hep3B人肝癌细胞系来研究TTR寡聚聚集体对EPO表达的影响。将Hep3B细胞与可溶性T寡核苷酸和寡聚TTR V30M孵育，并评估细胞增殖以及caspase 3/7活化。 EPO mRNA转录本的相对定量通过实时PCR进行。在低聚TTR V30M存在下24小时后，观察到细胞活力的显着降低（13 +/- 7.3％）和胱天蛋白酶3/7的激活。同样，在常氧条件下，EPO表达显着降低（50 +/- 2.8％）。利用与荧光素酶基因连接的EPO启动子的PCR片段构建了一个报告基因分析，以评估靶向该启动子的转录因子的作用。在暴露于TTR寡聚体的转染细胞中观察到EPO启动子活性显着降低（53 +/- 6.5％）。我们的结果表明，寡聚的TTR V30M至少部分通过抑制启动子活性来降低EPO表达。

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