Signal transducer and activator of transcription 3 activation up-regulates interleukin-6 autocrine production: a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells.
Signal transducer and activator of transcription 3 activation up-regulates interleukin-6 autocrine production: a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells.
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DOI：
10.1186/1476-4598-9-309
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发表时间：
2010-12-02
期刊：
影响因子：
37.3
通讯作者：
Su WC
中科院分区：
文献类型：
--
作者：
Huang WL;Yeh HH;Lin CC;Lai WW;Chang JY;Chang WT;Su WC
白细胞介素-6 （IL-6）的自发产生已在多种肿瘤中被观察到，并与癌症的发病、进展和耐药性有关。然而，癌细胞中IL-6自分泌的调控尚不完全清楚。IL-6在许多类型的细胞中是自动调节的。IL-6的三个主要下游通路中的两个，MEK/细胞外信号相关激酶（Erk）通路和磷脂酰肌醇3-激酶(PI3-K)/Akt通路，已被证明通过激活AP-1和NF-κB来调节IL-6的表达。然而，Janus kinase (Jak) 2/signal transducter and activator of transcription (Stat) 3 pathway的作用尚不清楚。本研究旨在确定Jak2/Stat3通路在癌细胞中调节IL-6自分泌的作用。Jak2/Stat3、MEK/Erk和PI3-K/Akt通路抑制剂下调肺腺癌PC14PE6/AS2 （AS2）细胞中IL-6的分泌，AS2细胞自发分泌IL-6并具有组成性激活的Stat3。转染显性阴性的Stat3、Stat3 siRNA或Stat3 shRNA可降低AS2细胞中IL-6的表达。相反，转染组成性激活的Stat3增加了IL-6的产生。在AS2衍生细胞中，对紫杉醇的耐药性与Stat3激活状态和IL-6的表达呈正相关，IL-6通常在耐药癌细胞中分泌。NF-κB、PI3-K/Akt和MEK/Erk的药理抑制以及Jak2/Stat3通路的药理抑制和遗传抑制（Stat3 siRNA）降低了各种耐药癌细胞系中IL-6自分泌量，同样降低了临床分离的肺癌细胞中IL-6自分泌量。这项研究是第一个直接解决Stat3在IL-6的自分泌产生中所起的作用，这是通过一个正反馈循环发生的。我们的生化和遗传学研究清楚地表明，Jak2/Stat3与其他IL-6下游途径结合，在广泛的癌细胞系和临床癌症样本中频繁和大量地促进IL-6自分泌。我们的研究结果表明Stat3可能被调节抑制癌细胞中IL-6自分泌，从而抑制癌症的进展并减少耐药性。
Spontaneous interleukin-6 (IL-6) production has been observed in various tumors and implicated in the pathogenesis, progression and drug resistance in cancer. However, the regulation of IL-6 autocrine production in cancer cells is not fully understood. IL-6 is auto-regulated in many types of cell. Two of the three major downstream pathways of IL-6, MEK/extracellular signal-related kinase (Erk) pathway and phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, have been shown to regulate IL-6 expression through the activation of AP-1 and NF-κB. However, it is not clear what the role of Janus kinase (Jak) 2/signal transducer and activator of transcription (Stat) 3 pathway. This study was designed to determine the role of Jak2/Stat3 pathway in the regulation of IL-6 autocrine production in cancer cells. Inhibitors of Jak2/Stat3, MEK/Erk and PI3-K/Akt pathways down-regulated IL-6 secretion in the lung adenocarcinoma PC14PE6/AS2 (AS2) cells, which spontaneously secreted IL-6 and possessed constitutively activated Stat3. Transfection with dominant-negative Stat3, Stat3 siRNA, or Stat3 shRNA decreased IL-6 expression in AS2 cells. Conversely, transfection with constitutively-activated Stat3 increased the production of IL-6. In AS2 derived cells, resistance to paclitaxel was positively correlated with Stat3 activation status and the expression of IL-6, which is commonly secreted in drug resistant cancer cells. The pharmacological inhibition of NF-κB, PI3-K/Akt and MEK/Erk and the pharmacological inhibition and genetic inhibition (Stat3 siRNA) of Jak2/Stat3 pathway decreased IL-6 autocrine production in various drug resistant cancer cell lines and similarly decreased IL-6 autocrine production in clinically isolated lung cancer cells. This study is the first to directly address the role Stat3 plays on the autocrine production of IL-6, which occurs through a positive-feedback loop. Our biochemical and genetic studies clearly demonstrated that Jak2/Stat3, in combination with other IL-6 downstream pathways, contributed frequently and substantially to IL-6 autocrine production in a broad spectrum of cancer cell lines as well as in clinical cancer samples. Our findings suggest that Stat3 could potentially be regulated to suppress IL-6 autocrine production in cancer cells to inhibit the progression of cancer and reduce drug resistance.
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影响因子：
29.4
作者：
Judd, Louise M.;Bredin, Karin;Giraud, Andrew S.
通讯作者：
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影响因子：
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