Interleukin-6 mediates G0/G1 growth arrest in hepatocellular carcinoma through a STAT 3-dependent pathway
Interleukin-6 mediates G0/G1 growth arrest in hepatocellular carcinoma through a STAT 3-dependent pathway
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DOI：
10.1016/j.jss.2007.04.022
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发表时间：
2008-06-01
影响因子：
2.2
通讯作者：
McKillop, Lain H.
中科院分区：
文献类型：
--
作者：
Moran, Dairmuid M.;Mattocks, M. Adrian;McKillop, Lain H.
白介素6(IL-6)是一种多效性细胞因子，调节多种细胞功能，包括增殖和分化。在肝脏内，IL-6信号在正常的肝脏生长和再生过程中起核心作用，但也可以抑制肝细胞癌(HCC)细胞的增殖。本研究的目的是确定IL-6诱导肝癌细胞周期停滞的潜在机制。这些研究表明，IL-6通过抑制细胞周期蛋白依赖性激酶(CDK)2和CDK4的活性而抑制细胞周期在G(0)/G(1)交界处的进展，而总的细胞周期蛋白(A、D1、D3和E)或CDK(CDK2、4和CDC2p34)的表达没有变化。抑制与IL-6受体激活相关的信号转导通路表明，IL-6依赖的G(0)-G(1)进程的抑制是通过Janus酪氨酸激酶信号转导和转录激活因子-3(JAK-STAT3)依赖的p21(waf1/cip1)诱导发生的，并且不依赖ERK-MAPK信号。这些数据表明，虽然IL-6在体内肝细胞启动和增殖中起中心作用，但在肝癌细胞中观察到的显著增殖抑制是由于IL-6-STAT3依赖于CDK2/CDK4活性和P21(waf1/cip1)表达的调节。(C)2008 Elsevier Inc.保留所有权利。
Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates diverse cell functions including proliferation and differentiation. Within the liver IL-6 signaling plays a central role during normal hepatic growth and regeneration yet can inhibit the proliferation of hepatocellular carcinoma (HCC) cells. The aim of the current study was to identify underlying mechanisms whereby IL-6 induces cell-cycle arrest in HCC cells. These studies demonstrate that IL-6 inhibits cell-cycle progression at the G(0)/G(1), interface through inhibition of cyclin-dependent kinase (cdk) 2 and cdk4 activity in the absence of changes in total cyclin (A, D1, D3, and E) or cdk (cdk2, 4, and cdc2 p34) expression. Inhibition of signal transduction pathways associated with IL-6 receptor activation demonstrates that IL-6-dependent inhibition of G(0)-G(1) progression occurs via Janus tyrosine kinase-signal transducers and activators of transcription-3 (Jak-STAT3)-dependent induction of p21(waf1/cip1) and is independent of ERK-MAPK signaling. These data demonstrate that, while IL-6 plays a central role in hepatocyte priming and proliferation in vivo, the pronounced inhibition of proliferation observed in HCC cells occurs due to IL-6-STAT3-dependent regulation of cdk2/cdk4 activity and P21(waf1/cip1) expression. (C) 2008 Elsevier Inc. All rights reserved.