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Prevention of liver cancer in chronic liver disease: An experimental study of sodium selenite and rat hepatocarcinogenesis

机译：预防慢性肝病中的肝癌：亚硒酸钠和大鼠肝癌发生的实验研究

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摘要

Selenium treatment in supranutritional but subtoxic doses has previously been shown to inhibit cell proliferation in preneoplastic lesions in a rat liver carcinogenesis model. The mechanisms are not known, but thioredoxin reductase (TrxR1), a seleno-enzyme essential for maintaining intracellular redox status and cellular defence against oxidative stress might be involved. The aim of this work was to study whether selenium affected regenerative liver growth after partial hepatectomy as it did neoplastic growth and to study the effect of selenium on TrxR1 expression and regulation in regenerative and normal rat liver. To address these questions, we have compared the effect of sodium selenite on tumour growth in an experimental rat liver model for the development of hepatocellular carcinoma with the effect of sodium selenite on regeneration of liver mass after 2/3 partial hepatectomy and the effect of 10 weeks sodium selenite treatment on normal rats.Sodium selenite administered in the drinking water (5μg/ml) reduced the rate of tumour growth during progression up to 12 months after initiation, but it did not affect gain of liver mass or rate of cell proliferation up to three weeks after 2/3 partial hepatectomy. Sodium selenite supplementation at dose levels of 1μg/ml and 5μg/ml showed an initial dose dependent increase of blood and liver levels of selenium. At 6 and 8 weeks, respectively, the selenium concentrations equilibrated regardless of dose and with no further accumulation. Sodium selenite did not affect body weight or relative liver mass at given doses.We also explored whether TrxR1 was a marker of the liver tumour phenotype or if the TrxR1 over expression found in liver preneoplasia and neoplasia could be explained only by TrxR1 induction in growing cells. We found that from 6 months after initiation in the tumour model TrxR1 was only expressed in neoplastic liver lesions that showed signs of cell proliferation (bromodeoxyuridine (BrdU) incorporation), while remodelling preneoplastic liver nodules that were BrdU negative were immunohistochemically negative for TrxR1. Both types of lesions were, however, expressing the classical marker of preneoplastic and neoplastic nodules, glutathione S-transferase π (GST-π). During liver cell regeneration TrxR1 was induced at the time of cell proliferation, but was back to background activity 72 hours after partial hepatectomy. Sodium selenite potentiated this increase in enzyme activity. When sodium selenite was given to normal rats over long time TrxR1 activity was induced in the liver to an extent reflecting the liver selenium levels. TrxR1 mRNA was, however, only increased over background at the time when the selenium level was increasing. We found that, although TrxR1 did increase to a certain extent during cell proliferation, the neoplastic over expression of TrxR1 was not correlated to the rate of cell growth in the tumours. Our interpretation of the finding that TrxR1 was selectively over expressed in the growing preneoplastic and neoplastic liver lesions is that TrxR1 is a tumour marker with a higher specificity to neoplasia with an increased risk for malignant transformation.Based on the facts that long-term treatment of selenite did not cause accumulation of selenium or selenium toxicity and the fact that selenium inhibited only neoplastic growth but not regenerative growth we suggest that selenium is a suitable candidate for tumour prevention in patients with chronic liver disease dependent on sustained ability of liver regeneration. Furthermore TrxR1 is a histological marker in chronic liver disease for liver cancer and liver cancer prestages with a potential to be a marker for liver cancer risk.
机译：先前已证明，在大鼠肝癌发生模型中，以超营养剂量但亚毒性剂量的硒治疗可抑制肿瘤前病变中的细胞增殖。该机制尚不清楚，但可能涉及硫氧还蛋白还原酶（TrxR1），一种维持细胞内氧化还原状态和抵抗氧化应激的细胞防御必需的硒酶。这项工作的目的是研究硒是否像部分肿瘤切除一样影响部分肝切除术后的再生肝生长，并研究硒对再生和正常大鼠肝脏中TrxR1表达和调控的影响。为了解决这些问题，我们比较了亚硒酸钠对实验性肝细胞癌大鼠肝模型中肿瘤生长的影响与亚硒酸钠对2/3部分肝切除术后肝肿块再生的影响以及10的影响。在正常大鼠中进行亚硒酸钠治疗的几周时间。饮用水中加入亚硒酸钠（5μg/ ml）可以降低肿瘤发作后直至开始后12个月内的肿瘤生长速率，但不会影响肝质量的获得或细胞增殖速率的提高2/3部分肝切除术后三周。剂量分别为1μg/ ml和5μg/ ml的亚硒酸钠显示血液和肝脏中硒的初始剂量依赖性增加。分别在第6周和第8周，硒浓度达到平衡，而与剂量无关，并且没有进一步的积累。亚硒酸钠在给定剂量下不会影响体重或相对肝脏质量。我们还探讨了TrxR1是否是肝肿瘤表型的标志物，或者是否只能通过TrxR1诱导在生长细胞中解释TrxR1在肝癌前病变和瘤形成中的过度表达。我们发现从肿瘤模型启动后6个月开始，TrxR1仅在显示细胞增殖迹象（溴脱氧尿嘧啶核苷（BrdU）掺入）的肿瘤性肝损伤中表达，而重塑BrdU阴性的肿瘤前肝结节则对TrxR1免疫组织化学阴性。然而，两种类型的病变均表达肿瘤前结节和肿瘤结节的经典标志物谷胱甘肽S-转移酶π（GST-π）。在肝细胞再生期间，TrxR1在细胞增殖时被诱导，但在部分肝切除术后72小时恢复到本底活动。亚硒酸钠增强了这种酶活性。将亚硒酸钠长时间给予正常大鼠后，肝脏中会诱导TrxR1活性达到反映肝脏硒水平的程度。然而，当硒水平增加时，TrxR1 mRNA仅比背景增加。我们发现，尽管TrxR1在细胞增殖过程中确实增加了一定程度，但肿瘤过度表达TrxR1与肿瘤中细胞的生长速率无关。我们对TrxR1在越来越多的肿瘤前和肿瘤性肝病灶中选择性表达的发现的解释是，TrxR1是对肿瘤的特异性更高的肿瘤标志物，恶性转化的风险增加。亚硒酸盐不会引起硒的积累或硒的毒性，并且硒仅抑制肿瘤生长而不抑制再生生长这一事实，我们认为硒取决于慢性肝再生能力，是慢性肝病患者预防肿瘤的合适候选药物。此外，TrxR1是慢性肝病中肝癌和肝癌前期的组织学标志物，有可能成为肝癌风险的标志物。

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    Erkhembayar Suvd;

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  • 年度 2011
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  • 正文语种 eng
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