Liver Research Center and Departments of Medicine and Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
Hepatol Res. 2008 Sep;38(9):940-53. doi: 10.1111/j.1872-034X.2008.00336.x. Epub 2008 Mar 10.
Insulin receptor substrate, type 1 (IRS-1) transmits growth and survival signals, and is overexpressed in more than 90% of hepatocellular carcinomas (HCCs). However, experimental overexpression of IRS-1 in the liver was found not to be sufficient to cause HCC. Since chronic alcohol abuse is a risk factor for HCC, we evaluated potential interactions between IRS-1 overexpression and chronic ethanol exposure by assessing premalignant alterations in gene expression.
Wild-type (wt) or IRS-1 transgenic (Tg) mice, constitutively overexpressing the human (h) transgene in the liver, were pair-fed isocaloric liquid diets containing 0% or 24% ethanol for 8 weeks. The livers were used for histopathologic study and gene expression analysis, focusing on insulin, insulin-like growth factor (IGF) and wingless (WNT)-Frizzled (FZD) pathways, given their known roles in HCC.
In wt mice, chronic ethanol exposure caused hepatocellular microsteatosis with focal chronic inflammation, reduced expression of proliferating cell nuclear antigen (PCNA) and increased expression of IGF-I and IGF-I receptor. In hIRS-1 Tg mice, chronic ethanol exposure caused hepatic micro- and macrosteatosis, focal chronic inflammation, apoptosis and disordered lobular architecture. These effects of ethanol in hIRS-1 Tg mice were associated with significantly increased expression of IGF-II, insulin, IRS-4, aspartyl-asparaginyl beta hydroxylase (AAH), WNT-1 and FZD 7, as occurs in HCC.
In otherwise normal liver, chronic ethanol exposure mainly causes liver injury and inflammation with impaired DNA synthesis. In contrast, in the context of hIRS-1 overexpression, chronic ethanol exposure may serve as a cofactor in the pathogenesis of HCC by promoting expression of growth factors, receptors and signaling molecules known to be associated with hepatocellular transformation.
胰岛素受体底物 1（IRS-1）传递生长和存活信号，在超过 90%的肝细胞癌（HCC）中过度表达。然而，实验中将 IRS-1 在肝脏中的过度表达发现不足以导致 HCC。由于慢性酒精滥用是 HCC 的一个危险因素，我们通过评估基因表达的癌前改变来评估 IRS-1 过度表达与慢性乙醇暴露之间的潜在相互作用。
将野生型（wt）或 IRS-1 转基因（Tg）小鼠，在肝脏中组成型过表达人（h）转基因，分别用等热量的含 0%或 24%乙醇的液体饮食进行配对喂养 8 周。将肝脏用于组织病理学研究和基因表达分析，重点关注胰岛素、胰岛素样生长因子（IGF）和无翅（WNT）-卷曲（FZD）途径，因为它们已知在 HCC 中起作用。
在 wt 小鼠中，慢性乙醇暴露导致肝细胞微脂肪变性伴局灶性慢性炎症，增殖细胞核抗原（PCNA）表达减少，IGF-I 和 IGF-I 受体表达增加。在 hIRS-1 Tg 小鼠中，慢性乙醇暴露导致肝微脂肪变性和大脂肪变性、局灶性慢性炎症、细胞凋亡和肝小叶结构紊乱。hIRS-1 Tg 小鼠中乙醇的这些作用与 IGF-II、胰岛素、IRS-4、天冬酰胺-β羟化酶（AAH）、WNT-1 和 FZD 7 的表达显著增加有关，这与 HCC 中发生的情况一致。
在其他方面正常的肝脏中，慢性乙醇暴露主要引起肝损伤和炎症，导致 DNA 合成受损。相比之下，在 hIRS-1 过度表达的背景下，慢性乙醇暴露可能通过促进与肝细胞转化相关的生长因子、受体和信号分子的表达，成为 HCC 发病机制的协同因素。
