Activation of NF-κB Is a Novel Target of KRAS-Induced Endometrial Carcinogenesis
Activation of NF-κB Is a Novel Target of KRAS-Induced Endometrial Carcinogenesis
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DOI：
10.1158/1078-0432.ccr-10-2291
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发表时间：
2011-03-15
影响因子：
11.5
通讯作者：
Inoue, Masaki
中科院分区：
文献类型：
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作者：
Mizumoto, Yasunari;Kyo, Satoru;Inoue, Masaki
目的：虽然KRAS突变是子宫内膜癌发生过程中的关键基因改变之一，但其下游靶点尚不清楚。实验设计：本研究利用端粒酶逆转录酶(TERT)永生化子宫内膜上皮细胞建立的致癌KRAS突变细胞，研究KRAS信号的分子靶点。结果：我们首次证实在KRAS致瘤细胞中激活了RAF-ERK通路，而不是PI3K-Akt通路。然而，将具有结构性活性的MAP/ERK激酶引入永生化细胞来模拟RAF-ERK的激活未能获得致癌表型，这表明KRAS触发的其他致癌途径的存在。最近发现的与KRAS信号相关联的证据促使我们研究了核因子-kappaB在子宫内膜癌发生中的作用。我们发现，与TERT永生化细胞相比，KRAS致瘤细胞中的核因子-kappa B的DNA结合活性明显增强。此外，在KRAS致瘤细胞中，NF-kappa B激活靶基因启动子的能力显著增强。通过引入一种耐降解的突变体I-kappa B，从而增强对核因子-kappa B的抑制作用，在很大程度上消除了KRAS致瘤细胞的转化表型。因此，致癌的KRAS信号通过激活核因子-kappaB的转录功能参与了子宫内膜细胞的致癌表型。结论：这些结果清楚地表明，核因子-kappaB的激活是致癌KRAS在子宫内膜癌发生中的一个新靶点，暗示了核因子-kappaB抑制剂在子宫内膜癌化学预防中的潜在应用，特别是在KRAS突变的情况下。临床癌症研究中心；17(6)；1341-50。(C)2011年AACR。
Purpose: Although the KRAS mutation is one of critical genetic alterations in endometrial carcinogenesis, the downstream targets are not known.Experimental Design: In this study, we investigated the molecular targets of KRAS signals, using tumorigenic cells with oncogenic KRAS mutation established from telomerase reverse transcriptase (TERT)immortalized endometrial epithelial cells.Results: We first confirmed that the RAF-ERK pathway, but not the PI3K-Akt pathway, was activated in KRAS tumorigenic cells. However, the introduction of constitutively active MAP/ERK kinase into immortalized cells to mimic RAF-ERK activation failed to obtain tumorigenic phenotypes, indicating the existence of other carcinogenic pathways triggered by KRAS. Recent evidence suggestive of linkage with KRAS signals prompted us to examine the involvement of NF-kappa B in endometrial carcinogenesis. We found that the DNA-binding activity of NF-kappa B was markedly elevated in KRAS tumorigenic cells compared with TERT-immortalized cells. Furthermore, the ability of NF-kappa B to activate the target gene promoters significantly increased in KRAS tumorigenic cells. Introduction of a mutant I kappa B that is resistant to degradation and thereby enhances the inhibitory effect on NF-kappa B largely abrogated the transformed phenotypes of KRAS tumorigenic cells. Thus, oncogenic KRAS signals contributed to the tumorigenic phenotypes of endometrial cells by activating the transcription function of NF-kappa B.Conclusions: These findings clearly show that NF-kappa B activation is a novel target of oncogenic KRAS in endometrial carcinogenesis, implying the potential utility of NF-kappa B inhibitors for endometrial cancer chemoprevention, especially with KRAS mutation. Clin Cancer Res; 17(6); 1341-50. (C)2011 AACR.