IL-11 contribution to tumorigenesis in an NRF2 addiction cancer model
IL-11 contribution to tumorigenesis in an NRF2 addiction cancer model
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DOI：
10.1038/onc.2017.236
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发表时间：
2017-11-09
期刊：
影响因子：
8
通讯作者：
Motohashi, H.
中科院分区：
文献类型：
--
作者：
Kitamura, H.;Onodera, Y.;Motohashi, H.
癌细胞与其微环境之间的相互作用是癌症病理性质的重要决定因素，特别是它们的致瘤能力。KEAP1-NRF2系统最初被认为是抗氧化应激的关键防御机制，在形成实体瘤的各种人类癌症中经常失调，导致NRF2的异常激活。NRF2在癌症中的积累增加与癌症患者（包括肺癌和乳腺癌患者）的不良预后密切相关。多种证据表明，癌细胞中异常激活的NRF2驱动了它们的恶性进展，癌细胞因此产生了“NRF2成瘾”。尽管NRF2的下游效应物已被广泛研究，但NRF2激活如何促进侵袭性肿瘤发生的机制仍有待阐明。在本研究中，我们发现NRF2与乳腺癌患者IL-11状态之间存在显著相关性。基于最近的一份报告表明IL-11在NRF2下游被诱导，我们通过新建立的NRF2成瘾癌模型检验了IL-11在NRF2驱动的肿瘤发生中的意义。在NRF2成瘾癌模型的肿瘤发生过程中，il - 11的表达水平升高，但在体外培养的肿瘤模型细胞中几乎检测不到il - 11的表达。这些结果表明，来自微环境的信号与NRF2合作激活il - 11。据我们所知，这是首次报道微环境对癌细胞中NRF2通路的影响以及NRF2对癌症分泌表型的贡献。在NRF2成瘾癌模型中破坏IL-11可显著抑制肿瘤发生，提示IL-11在NRF2驱动的肿瘤发生中发挥重要作用。因此，本研究提示IL-11是nrf2依赖性乳腺癌的潜在治疗靶点。
The interaction between cancer cells and their microenvironment is an important determinant of the pathological nature of cancers, particularly their tumorigenic abilities. The KEAP1-NRF2 system, originally identified as a critical defense mechanism against oxidative stress, is often dysregulated in various human cancers forming solid tumors, resulting in the aberrant activation of NRF2. Increased accumulation of NRF2 in cancers is strongly associated with the poor prognoses of cancer patients, including those with lung and breast cancers. Multiple lines of evidence suggest that aberrantly activated NRF2 in cancer cells drives their malignant progression and that the cancer cells consequently develop 'NRF2 addiction.' Although the downstream effectors of NRF2 that are responsible for cancer malignancy have been extensively studied, mechanisms of how NRF2 activation contributes to the aggressive tumorigenesis remains to be elucidated. In this study, we found a significant correlation between NRF2 and IL-11 status in breast cancer patients. Based on a recent report demonstrating that IL-11 is induced downstream of NRF2, we examined the significance of IL-11 in NRF2-driven tumorigenesis with a newly established NRF2 addiction cancer model. Expression of Il11 was elevated during the tumorigenesis of the NRF2 addiction cancer model, but intriguingly, it was hardly detected when the cancer model cells were cultured in vitro. These results imply that a signal originating from the microenvironment cooperates with NRF2 to activate Il11. To the best of our knowledge, this is the first report showing the influence of the microenvironment on the NRF2 pathway in cancer cells and the contribution of NRF2 to the secretory phenotypes of cancers. Disruption of Il11 in the NRF2 addiction cancer model remarkably inhibited the tumorigenesis, suggesting an essential role of IL-11 in NRF2-driven tumorigenesis. Thus, this study suggests that IL-11 is a potential therapeutic target for NRF2-addicted breast cancers.