Upregulation of the Insulin Receptor and Type I Insulin-Like Growth Factor Receptor Are Early Events in Hepatocarcinogenesis
Upregulation of the Insulin Receptor and Type I Insulin-Like Growth Factor Receptor Are Early Events in Hepatocarcinogenesis
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DOI：
10.1177/0192623310396905
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发表时间：
2011-04-01
影响因子：
1.5
通讯作者：
Bannasch, Peter
中科院分区：
文献类型：
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作者：
Aleem, Eiman;Nehrbass, Dirk;Bannasch, Peter
肝细胞癌（HCC）发生的分子机制尚未完全清楚。在不同物种中，改变的肝细胞的癌前病灶规律地先于HCC。改变的肝细胞的主要最早类型的病灶，糖原储存病灶（GSF），显示细胞质中糖原过量（糖原沉积）。在从GSF进展到HCC的过程中，储存的糖原逐渐减少，导致嗜碱性HCC完全丧失。我们以前已经表明，在N-亚硝基吗啉诱导的肝癌，胰岛素受体底物（IRS-1）在GSF中强烈表达，并在HCC进展过程中减少，从而与糖原含量。在本研究中，我们观察到GSF中胰岛素受体、IGF-I受体（IGF-IR）、IRS-2和丝裂原活化激酶/细胞外调节激酶-1水平升高，其表达模式与IRS-1相同。我们的结论是IRS-1，IRS-2，和丝裂原活化激酶/细胞外调节激酶-1的丰度一致的一致上调IR和IGF-IR诱导的肝癌。我们的数据表明，在早期肝细胞癌前病变中，IR通过IRS-1和/或IRS-2上调，而IGF-IR水平的增加可能导致GSF中先前报道的细胞增殖增加。因此，IR和IGF-IR的协同上调可能代表肝癌发生的初始事件。
The molecular mechanisms underlying the development of hepatocellular carcinoma (HCC) are not yet fully understood. Preneoplastic foci of altered hepatocytes regularly precede HCC in various species. The predominant earliest type of foci of altered hepatocytes, the glycogen storage focus (GSF), shows an excess of glycogen (glycogenosis) in the cytoplasm. During progression from GSF to HCC, the stored glycogen is gradually reduced, resulting in complete loss in basophilic HCC. We have previously shown that in N-nitrosomorpholine-induced hepatocarcinogenesis, insulin receptor substrate (IRS-1) is strongly expressed in GSF and reduced during progression to HCC, thus correlating with the glycogen content. In the present study, we observed increased levels of insulin receptor, IGF-I receptor (IGF-IR), IRS-2, and mitogen-activated kinase/extracellular regulated kinase-1 in GSF, following the same pattern of expression as IRS-1. We conclude that the abundance of IRS-1, IRS-2, and mitogen-activated kinase/extracellular regulated kinase-1 coincides with a concerted upregulation of both IR and IGF-IR induced by the hepatocarcinogen. Our data suggest that in early hepatocellular preneoplasia, the upregulation of IR elicits glycogenosis through IRS-1 and/or IRS-2, whereas the increased level of the IGF-IR may lead to the increased cell proliferation previously reported in GSF. Therefore, the concerted upregulation of both IR and IGF-IR may represent initial events in hepatocarcinogenesis.