Cancer testis antigen 55 deficiency attenuates colitis-associated colorectal cancer by inhibiting NF-kappa B signaling
Cancer testis antigen 55 deficiency attenuates colitis-associated colorectal cancer by inhibiting NF-kappa B signaling
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癌症睾丸抗原 55 缺乏症通过抑制 NF-kappaB 信号传导减弱结肠炎相关结直肠癌
DOI：
10.1038/s41419-019-1537-x
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发表时间：
2019
影响因子：
9
通讯作者：
Zhang Xiao Dong
中科院分区：
文献类型：
--
作者：
Zhao Huan;Pan Wen Ming;Zhang Hui Hui;Song Yang;Chen Jie;Xiang Ying;Gu Bo;Li Shang Ze;Du Run Lei;Zhang Xiao Dong
结肠炎相关癌（CAC）是一种炎症相关癌的原型，是最常见的胃肠道肿瘤之一。癌睾丸抗原55（cancer testis antigen 55，CT 55）是一种潜在的癌睾丸抗原，在多种肿瘤和正常睾丸中均有表达。然而，其在CAC中的作用仍然未知。在这里，我们确定CT 55作为一个新的有效的CAC启动子。我们发现，Ct 55缺陷减轻炎症反应，减少细胞增殖和结肠炎相关的肿瘤发生在氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）小鼠模型。在机制上，CT 55作为肿瘤坏死因子（TNF）-α诱导的核因子-κB（NF-κB）信号传导的加速剂。在TNF-α刺激后，CT 55与IκB激酶（IKK）复合物相互作用，增加IKKα/β的磷酸化并激活IKK-p65信号传导，而敲除CT 55则阻断IKK-p65信号传导。值得注意的是，IKK的抑制消除了CT 55对NF-κB活化的积极作用。总的来说，我们的研究结果强烈表明，CT 55缺陷抑制CAC的发展，CT 55-TNF-α诱导的NF-κB轴可能是CAC治疗的一个有希望的靶点。
Colitis-associated cancer (CAC), a prototype of inflammation-associated cancer, is one of the most common gastrointestinal tumors. As a potential cancer testis antigen (CT antigen), cancer testis antigen 55 (CT55) is expressed in different tumors and normal testes. However, its role in CAC remains unknown. Here, we identified CT55 as a new potent promoter of CAC. We discovered that Ct55 deficiency alleviated inflammatory responses, decreased cell proliferation and colitis-associated tumorigenesis in an azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model. Mechanistically, CT55 acts as an accelerator of tumor necrosis factor (TNF)-α-induced nuclear factor-κB (NF-κB) signaling. Upon stimulation with TNF-α, CT55 interacts with the IκB kinase (IKK) complex, which increases the phosphorylation of IKKα/β and activates IKK–p65 signaling, while knockout of CT55 blocks IKK–p65 signaling. Notably, inhibition of IKK abolished the positive effect of CT55 on NF-κB activation. Collectively, our findings strongly indicate that CT55 deficiency suppresses the development of CAC and that the CT55-TNF-α-induced NF-κB axis may represent a promising target for CAC therapy.