Pyruvate kinase isoenzyme shift from L-type to M2-type is a late event in hepatocarcinogenesis induced in rats by a choline-deficient/DL-ethionine-supplemented diet
Pyruvate kinase isoenzyme shift from L-type to M2-type is a late event in hepatocarcinogenesis induced in rats by a choline-deficient/DL-ethionine-supplemented diet
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DOI：
10.1093/carcin/19.1.99
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发表时间：
1998-01-01
期刊：
影响因子：
4.7
通讯作者：
Bannasch, P
中科院分区：
文献类型：
--
作者：
Hacker, HJ;Steinberg, P;Bannasch, P
用含0.1%（w/w）DL-乙醇胺（CDE）的胆碱缺乏饲料喂养大鼠4、10、14或22周，另一组用CDE处理4周，然后用正常饲料喂养4周。治疗4周后，肝细胞中的L-PK表达强烈降低，并保持较低水平直至研究结束，与未处理的对照相比，在数周后停止CDE，随后4周正常饮食导致L-PK表达几乎完全恢复，在后期阶段（CDE治疗10-22周），观察到许多假小叶、改变的肝细胞（FAH）的癌前病灶，如透明/嗜酸性细胞病灶（CCF/ACF）和混合/嗜碱性细胞病灶（MCF/BCF），以及肝细胞腺瘤（HCA）。假小叶显示L-PK表达轻微降低，M-2-PK阴性。在过度储存糖原的CCF/ACF的所有透明细胞组分中，与对照的周围实质和肝细胞相比，L-PK表达增加。在糖原储存不太明显的嗜酸性细胞组分中，L-PK表达与假小叶的表达相似，显示该酶蛋白的含量略有减少，CCF/ACF中的M-2-PK总是阴性，在大多数MCF中，糖原储存亚群表达L-PK，而在所有糖原贫乏的嗜碱性群体中，L-PK蛋白强烈降低，M-2-PK在大多数这些MCF中不表达。然而，在罕见的MCF中，L-PK表达的减少与M-2-PK的显著表达相结合。在HCA中，M-2-PK进一步增加，尽管程度不同，而L-PK仍然强烈降低。我们的研究结果表明，在肝癌发生的晚期阶段，从L-PK到M-2-PK的同工酶转变发生了，那些L-PK表达低和M-2-PK再表达的MCF最可能代表肝细胞肿瘤的直接前驱病变。
Rats received a choline-deficient diet containing 0.1% (w/w) DL-ethionine (CDE) for 4, 10, 14 or 22 weeks, A separate group was treated for 4 weeks with CDE and then received a normal diet for 4 weeks, The L and M-2 isoenzymes pyruvate kinase mere immunocytochemically demonstrated in liver sections, L-PK expression was strongly reduced in the hepatocytes after 4 weeks of treatment and remained low until the end of the study, Withdrawal of CDE after weeks followed by 4 weeks normal diet resulted in a nearly full recovery of L-PK expression as compared to untreated controls, At later stages (10-22 weeks of CDE-treatment) many pseudolobules, preneoplastic foci of altered hepatocytes (FAH) such as combined clear/acidophilic cell foci (CCF/ACF) and mixed/basophilic cell foci (MCF/BCF), and hepatocellular adenomas (HCA) were observed, Pseudolobules showed a slight reduction in L-PK-expression, and were negative for M-2-PK. In all clear cell components of CCF/ACF excessively storing glycogen, L-PK-expression was increased compared to both the surrounding parenchyma and hepatocytes of controls, In acidophilic cell components with less pronounced glycogen storage L-PK expression was similar to that of pseudolobules showing a slightly reduced content of this enzyme protein, M-2-PK was invariably negative in CCF/ACF, In most MCF glycogen-storing subpopulations expressed L- PK, whereas in all glycogen-poor basophilic populations L-PK protein was strongly reduced, M-2-PK was not expressed in most of these MCF. However, in rare MCF the reduction in L-PK expression was combined with significant expression of M-2-PK. In HCA M-2-PK underwent a further increase, although to a variable degree, while L-PK remained strongly reduced, Our results show that an isoenzyme shift from L-PK to M-2-PK takes place at a late stage of the hepatocarcinogenic process, and that those MCF with a low L-PK expression and a reexpression of M-2-PK most probably represent the direct precursor lesions of hepatocellular neoplasms.