Department of Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, California 90033, USA.
J Gastroenterol Hepatol. 2013 Mar;28(3):576-83. doi: 10.1111/jgh.12084.
Hepatocellular adenomas (HCAs) are benign tumors that can lead to medical complications. Chronic inflammation and mutations in β-catenin, hepatocyte nuclear factor 1α, or glycoprotein 130 are potential causes for human HCA. However, additional causes may exist due to heterogeneity of HCA. We investigated whether HCA are caused by endoplasmic reticulum (ER) stress.
Mice with a liver-specific deletion of the major chaperone BiP (LGKO) were used. Liver tumor occurrence was examined in LGKO with or without feeding of a high-fat diet (HFD) and characterized with immunohistochemistry with molecular markers of proliferation/malignancy. Molecular changes were analyzed with immunoblotting.
Spontaneous monoclonal liver tumors were observed in 34% of LGKO females with constitutive hepatic ER stress. Lack of portal tracks or central veins, dilated sinusoidal spaces, hemorrhagic areas, active proliferation, and lipid deposits were observed in the liver tumors. HFD feeding induced multiclonal liver tumors in 83% of the LGKO females versus 0 in wild-type females. Hepatocytes reactive to antiglypican 3 antibodies were detected in the HFD-induced, but not spontaneous, tumors. In the liver tumors, inhibition of cyclin D and increase of the 36 kD estrogen receptor variant (estrogen receptor α36), active transcription activator 4/6, glycogen synthase kinase 3β, and extracellular signal-regulated protein kinases 1 and 2 were detected, whereas no change of hepatocyte nuclear factor 1α, β-catenin, p-53, androgen receptor α, or estrogen receptor α was detected. HFD activated Janus kinase and signal transducers and activators of transcription 3.
Our evidence supports a novel link of HCA with ER stress and altered expression of cyclin D and estrogen receptor α36. Additional stress such as HFD may promote malignant transformation of HCA through the Janus kinase-signal transducers and activators of transcription pathway.
肝细胞腺瘤（HCA）是一种良性肿瘤，可导致医疗并发症。β-连环蛋白、肝细胞核因子 1α 或糖蛋白 130 的慢性炎症和突变是人类 HCA 的潜在原因。然而，由于 HCA 的异质性，可能存在其他原因。我们研究了内质网（ER）应激是否会导致 HCA。
使用肝脏特异性缺失主要伴侣 BiP（LGKO）的小鼠。检查 LGKO 是否存在或不存在高脂肪饮食（HFD）喂养时的肝肿瘤发生，并通过免疫组化用增殖/恶性的分子标志物进行特征描述。用免疫印迹分析分子变化。
在具有组成性肝 ER 应激的 LGKO 雌性小鼠中观察到自发的单克隆肝肿瘤，发生率为 34%。在肝肿瘤中观察到缺乏门脉轨道或中心静脉、扩张的窦状空间、出血区、活跃增殖和脂质沉积。HFD 喂养在 83%的 LGKO 雌性小鼠中诱导多克隆肝肿瘤，而在野生型雌性小鼠中为 0。在 HFD 诱导的肿瘤中检测到对抗糖蛋白 3 抗体反应的肝细胞，但在自发肿瘤中未检测到。在肝肿瘤中，检测到细胞周期蛋白 D 的抑制和 36kD 雌激素受体变体（雌激素受体 α36）、活性转录激活物 4/6、糖原合酶激酶 3β 和细胞外信号调节蛋白激酶 1 和 2 的增加，而没有检测到肝细胞核因子 1α、β-连环蛋白、p-53、雄激素受体 α 或雌激素受体 α 的变化。HFD 激活了 Janus 激酶和信号转导子和转录激活子 3。
我们的证据支持 HCA 与 ER 应激和细胞周期蛋白 D 及雌激素受体 α36 表达改变之间存在新的联系。HFD 等额外应激可能通过 Janus 激酶-信号转导子和转录激活子途径促进 HCA 的恶性转化。
