生物
目标2
炎症体
雷布
基因敲除
宫颈癌
先天免疫系统
上睑下垂
癌症研究
免疫
炎症
癌症
癌变
免疫学
免疫系统
细胞凋亡
转录因子
基因
遗传学
NFKB1型
作者
Daeho So,Hyun‐Woo Shin,Jiyoung Kim,Mingyu Lee,Jongyun Myeong,Yang Sook Chun,Jong-Wan Park
出处
期刊:Oncogene
[Springer Nature]
日期:2018-05-29
卷期号:37 (38): 5191-5204
被引量:65
标识
DOI:10.1038/s41388-018-0339-4
摘要
Mammalian cells are equipped with antiviral innate immunity. To survive and grow, human papilloma virus (HPV)-infected cervical cancer cells must overcome this host defense system. However, the precise mechanism whereby cervical cancer cells evade the immunity is not fully understood. We noted that Sirtuin 1 (SIRT1) is overexpressed in HPV-infected cervical cancer cells and hypothesized that SIRT1 counteracts antiviral immunity. Here, we found that cervical cancer cells undergo massive death by SIRT1 knockdown, but this effect is reversed by SIRT1 restoration. SIRT1-knocked-down cells showed representative features of pyroptosis, as well as highly expressed absent in melanoma 2 (AIM2) and its downstream genes related to the inflammasome response. Mechanistically, SIRT1 repressed the NF-κB-driven transcription of the AIM2 gene by destabilizing the RELB mRNA. Interestingly, pyroptotic death signaling in SIRT1-knocked-down cells was transmitted to naive cervical cancer cells, which was mediated by extracellular vesicles carrying AIM2 inflammasome proteins. Furthermore, the growth of cervical cancer xenografts was significantly inhibited by either SIRT1-targeting siRNAs or SIRT1-knockdown-derived extracellular vesicles. Immunohistochemical analyses showed that SIRT1 expression correlated with poor clinical outcomes in cervical cancer. In conclusion, SIRT1 enabled HPV-infected cervical cancer cells to continue growing by nullifying AIM2 inflammasome-mediated immunity. Without SIRT1, cervical cancer cells could no longer survive because of the derepression of the AIM2 inflammasome. SIRT1 could therefore be a target for the effective treatment of cervical cancer.
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