Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes
Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes
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DOI：
10.1016/j.jhep.2005.10.030
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发表时间：
2006-06-01
影响因子：
25.7
通讯作者：
Patel, Tushar
中科院分区：
文献类型：
--
作者：
Meng, Fanyin;Yamagiwa, Yoko;Patel, Tushar
背景/目的：IL-6的过度表达与胆管癌的生长有关，但涉及的细胞机制尚不清楚。我们的目的是评估IL-6过表达促进恶性胆管细胞转化细胞生长的机制。方法：稳定转染过表达IL-6的细胞系来源于恶性人胆管细胞。通过体外锚定非依赖性生长和裸鼠异种移植物生长评估转化细胞生长。通过免疫印迹分析和实时PCR定量抗凋亡蛋白Mcl-1的表达。使用siRNA进行基因沉默。显性负上游激酶激活剂和亚型特异性结构被用来评估参与p38 MAP激酶信号转导pathways.Results：过度表达IL-6增加异种移植物的生长，锚定独立的生长和细胞存活，但没有显着改变细胞增殖。在IL-6过表达的细胞中，Mcl-1的基础表达增加。通过siRNA选择性敲低Mcl-1增加吉西他滨诱导的细胞毒性。此外，IL-6通过p38 MAPK依赖mechanism.Conclusions增加Mcl-1 mRNA和蛋白表达：这些数据表明，在介导IL-6过度表达的影响，在胆管癌生长的生存信号通路的主要作用。Mcl-1被鉴定为IL-6诱导的肿瘤细胞存活的介质，并且显示通过p38 MAPK依赖性途径由IL-6转录调节。我们的结论是，IL-6介导的生存信号通路的调制涉及p38 MAPK或下游目标，如Mcl-1可能证明有用的治疗策略，为人类胆管癌。(c)2005年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: Over-expression of IL-6 has been implicated in cholangiocarcinoma growth but the cellular mechanisms involved are unknown. Our aims were to assess the mechanisms by which over-expression of IL-6 promotes transformed cell growth in malignant cholangiocytes.Methods: Stably transfected cell lines over-expressing IL-6 were derived from malignant human cholangiocytes. Transformed cell growth was assessed by anchorage independent growth in vitro and by xenograft growth in nude mice. Expression of the anti-apoptotic protein Mcl-1 was quantitated by immunoblot analysis and by real-time PCR. Gene silencing was performed using siRNA. Dominant negative upstream kinase activators and isoform-specific constructs were used to evaluate the involvement of p38 MAP kinase signaling pathways.Results: Over-expression of IL-6 increased xenograft growth, anchorage independent growth and cell survival but did not significantly alter cell proliferation. The basal expression of Mcl-1 was increased in IL-6 over-expressing cells. Selective knockdown of Mcl-1 by siRNA increased gemcitabine-induced cytotoxicity. Moreover, IL-6 increased Mcl-1 mRNA and protein expression via a p38 MAPK dependent mechanism.Conclusions: These data demonstrate a major role of survival signaling pathways in mediating the effects of IL-6 over-expression in cholangiocarcinoma growth. Mcl-1 is identified as a mediator of IL-6-induced tumor cell survival and shown to be transcriptionally regulated by IL-6 via a p38 MAPK dependent pathway. We conclude that modulation of IL-6 mediated survival signaling pathways involving the p38 MAPK or downstream targets such as Mcl-1 may prove useful therapeutic strategies for human cholangiocarcinoma. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.