TLR4 activates NF-κB in human ovarian granulosa tumor cells.
TLR4 activates NF-κB in human ovarian granulosa tumor cells.
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DOI：
10.1016/j.bbrc.2011.05.063
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发表时间：
2011-06-17
影响因子：
3.1
通讯作者：
Johnson, A. L.
中科院分区：
文献类型：
--
作者：
Woods, Dori C.;White, Yvonne A. R.;Dau, Caroline;Johnson, A. L.
以往的研究表明，Toll样受体（TLR）的表达在正常卵巢（OSE）和上皮性卵巢肿瘤的表面上皮。最值得注意的是，OSE衍生的癌症表达TLR 4，其激活核因子-κ B（NF-κB）信号级联作为炎症反应的介质。目前，人们对阐明TLR介导的信号传导在癌症中的作用非常感兴趣。然而，在卵巢颗粒细胞瘤（GCT）中TLR的表达，以及GCT表达TLR可能影响细胞信号传导途径和/或调节化疗药物疗效的程度，尚未确定。在本研究中，利用人GCT细胞系（COV 434和KGN）来评估功能性TLR 4的表达。TLR 4在GCT细胞系中表达，并且TLR 4与细菌脂多糖（LPS）连接导致IκB降解和NF-κB活化。通过用LPS和天然存在的配体HSP 60处理后NF-κB p65的核定位来证实NF-κB活化。值得注意的是，TLR 4的免疫中和阻断了核定位，NF-κB信号传导的抑制减弱了LPS诱导的TNFα，并增加了两种细胞系的倍增时间。与使用人OSE细胞系的报道相反，NF-κB信号传导的抑制未能使GCT系对TRAIL或顺铂敏感。总之，本文的发现首次证明了GCT中特异性的功能性TLR信号传导途径，并表明与OSE衍生的癌症相反，NF-κB的抑制不会使GCT对TRAIL或顺铂敏感。
Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (OSE) and in epithelial ovarian tumors. Most notably, OSE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-κB) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to IκB degradation and activation of NF-κB. NF-κB activation was confirmed by nuclear localization of NF-κB p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-κB signaling attenuated LPS-induced TNFαplus increased doubling time in both cell lines. Contradictory to reports using human OSE cell lines, inhibition of NF-κB signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to OSE-derived cancers, inhibition of NF-κB does not sensitize GCTs to TRAIL or cisplatin.
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DOI：
10.1158/1078-0432.ccr-10-3265
发表时间：
2011-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Yang G;Xiao X;Rosen DG;Cheng X;Wu X;Chang B;Liu G;Xue F;Mercado-Uribe I;Chiao P;Du X;Liu J
通讯作者：
Liu J
影响因子：
9.7
作者：
Woods, Dori C.;Liu, Han-Ken;Johnson, A. L.
通讯作者：
Johnson, A. L.
影响因子：
4
作者：
Zhang, H;Vollmer, M;De Geyter, C
通讯作者：
De Geyter, C
影响因子：
11.2
作者：
Kelly, MG;Alvero, AB;Mor, G
通讯作者：
Mor, G
影响因子：
13.5
作者：
Yamanaka, T;Shiraki, K;Suzuki, A
通讯作者：
Suzuki, A