Interleukin-6 inhibits cell proliferation in a rat model of hepatocellular carcinoma
Interleukin-6 inhibits cell proliferation in a rat model of hepatocellular carcinoma
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DOI：
10.1111/j.1478-3231.2005.01083.x
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发表时间：
2005-04-01
影响因子：
6.7
通讯作者：
McKillop, IH
中科院分区：
文献类型：
--
作者：
Moran, DM;Mayes, N;McKillop, IH
背景：白细胞介素-6（IL-6）在肝脏的正常生长和再生中起着重要作用。本研究的目的是确定在肝细胞癌（HCC）的体内模型中的IL-6信号传导的组分的表达，并解决IL-6信号传导在HCC的进展中的作用。研究方法：建立大鼠肝癌模型，检测肝癌组织和正常肝组织中IL-6受体（IL-6 R）及其下游信号通路的表达和活性。然后分离来自切除的HCC样品和正常肝细胞的致瘤性HCC细胞，并在存在和不存在重组人IL-6（rhIL-6）的情况下培养。结果：与正常肝组织相比，肝癌组织中IL-6 R α/gp 130表达明显降低。相比之下，HCC样品具有显著增加的IL-6信使RNA表达和信号转导和转录激活因子（STAT）3活性。使用体外细胞培养，我们证明，IL-6刺激STAT 3和细胞外调节激酶（ERK）在肝癌细胞和分离的肝细胞的活性。然而，虽然STAT 3激活模式相似，但IL-6在HCC细胞中以双相方式刺激ERK活性，在肝细胞中以双相持续ERK激活。在HCC细胞中，细胞周期蛋白依赖性激酶（CDK）抑制剂，p21（waf 1/cip 1）和p27（Kip 1）的显着诱导发生，在正常肝细胞中没有观察到的效果。最后，我们建立了IL-6抑制血清刺激的DNA合成和细胞有丝分裂在体外肝癌细胞。结论：这些数据表明在体内肝癌中IL-6信号传导组分的表达改变。HCC细胞的IL-6处理抑制血清刺激的有丝分裂发生，这可能是通过细胞内信号传导途径的活化谱的差异及其对CDK抑制剂表达/活性的影响。
Background: Interleukin-6 (IL-6) plays a critical role in normal hepatic growth and liver regeneration. The aims of the present study are to determine the expression of components of IL-6 signaling in an in vivo model of hepatocellular carcinoma (HCC) and address the role of IL-6 signaling in the progression of HCC. Methods: An in vivo rat HCC model was established and IL-6 receptor (IL-6R) and downstream signaling pathway expression and activity were determined in HCC and normal liver specimens. Tumorigenic HCC cells from resected HCC samples and normal hepatocytes were then isolated and cultured in the presence and absence of recombinant human IL-6 (rhIL-6). Results: HCC specimens demonstrated decreased IL-6R alpha/gp130 expression as compared with the normal liver. In contrast, HCC samples had significantly increased IL-6 messenger RNA expression and signal transducers and activators of transcription (STAT)3 activity. Using in vitro cell cultures, we demonstrated that IL-6 stimulated STAT3 and extracellular regulated kinase (ERK) activity in both HCC cells and isolated hepatocytes. However, while STAT3 activation profiles were similar, IL-6 stimulated ERK activity in a biphasic manner in HCC cells and a monophasic, sustained ERK activation in hepatocytes. In HCC cells, a significant induction of cyclin-dependent kinase (CDK) inhibitors, p21(waf1/cip1) and p27(Kip1) occurred, an effect that was not observed in normal hepatocytes. Finally, we established that IL-6 acted to inhibit serum-stimulated DNA synthesis and cell mitogenesis in HCC cells in vitro. Conclusions: These data demonstrate altered expression of components of IL-6 signaling in HCC in vivo. IL-6 treatment of HCC cells inhibits serum-stimulated mitogenesis, possibly via differences in activation profiles of intracellular signaling pathways and their effect on CDK inhibitor expression/activity.