LncRNA PCAT1 activates SOX2 and suppresses radioimmune responses via regulating cGAS/STING signalling in non-small cell lung cancer.
LncRNA PCAT1 activates SOX2 and suppresses radioimmune responses via regulating cGAS/STING signalling in non-small cell lung cancer.
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LncRNA PCAT 1通过调节cGAS/STING信号转导激活SOX 2并抑制非小细胞肺癌中的放射免疫反应。
DOI：
10.1002/ctm2.792
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发表时间：
2022-04
影响因子：
10.6
通讯作者：
Xie, Conghua
中科院分区：
文献类型：
--
作者：
Gao, Yanping;Zhang, Nannan;Zeng, Zihang;Wu, Qiuji;Jiang, Xueping;Li, Shuying;Sun, Wenjie;Zhang, Jianguo;Li, Yangyi;Li, Jiali;He, Fajian;Huang, Zhengrong;Zhang, Jinfang;Gong, Yan;Xie, Conghua
在非小细胞肺癌(NSCLC)中，前列腺癌相关的长非编码RNA(LncRNA)转录本1(PCAT1)的表达增加。它刺激肿瘤生长和转移，但其在放射免疫反应中的作用尚不清楚。我们旨在探讨PCAT1在非小细胞肺癌中对肿瘤发生和放射免疫反应的影响及其潜在的分子机制。综合生物信息学分析确定免疫抑制的lncRNAs与非小细胞肺癌的肿瘤侵袭有关。用原位杂交法分析55例配对的非小细胞肺癌组织和癌旁正常组织中PCAT1的表达水平。采用功能丧失和功能获得两种方法检测PCAT1和SOX2在体内和体外对NSCLC细胞行为的影响。通过生物信息学分析、染色质RNA纯化(CHIRP)和双荧光素酶报告实验验证PCAT1对SOX2表达的调控作用。染色质免疫沉淀、荧光素酶和补救试验用于确定SOX2与干扰素基因的cGAS/刺激物(STING)信号的关系。PCAT1具有免疫抑制作用，与NSCLC的侵袭有关。NSCLC中PCAT1升高与免疫细胞浸润呈负相关。PCAT1基因敲除抑制了细胞的增殖，增加了细胞的凋亡率，并抑制了体内和体外的细胞转移。PCAT1激活SOX2，加速肿瘤形成和免疫抑制。SOX2通过抑制细胞毒性T细胞免疫促进肿瘤生长。此外，SOX2还抑制了cGAS的转录，并阻碍了下游I型干扰素诱导的免疫反应。抑制PCAT1/SOX2结合放射治疗进一步抑制肿瘤生长，启动cGAS/STING信号通路，增强非小细胞肺癌放射治疗的免疫应答。PCAT1/SOX2轴通过抑制cGAS/STING信号转导的T细胞活化促进肿瘤的发生和免疫抑制。抑制PCAT1和SOX2与放射治疗协同激活免疫反应，可作为潜在的治疗靶点。LncRNA PCAT1通过下调cGAS/STING信号通路在非小细胞肺癌中高表达免疫抑制作用。LncRNA PCAT1上调SOX2转录，SOX2下调cGAS转录。LncRNA PCAT1通过SOX2/cGAS/STING途径抑制放射免疫反应，其下调增强了放射治疗对非小细胞肺癌的抑制作用。
The expression of long non‐coding RNA (lncRNA) prostate cancer‐associated ncRNA transcripts 1 (PCAT1) is increased in non‐small cell lung cancer (NSCLC). It stimulates tumour growth and metastasis, but its role in the radioimmune responses remain unknown. We aimed to explore the impacts of PCAT1 on tumorigenesis and radioimmune responses and the underlying molecular mechanisms in NSCLC. Comprehensive bioinformatics analysis was performed to identify immunosuppressive lncRNAs involved with tumour invasion in NSCLC. The expression levels of PCAT1 were analysed by in situ hybridisation in 55 paired NSCLC tissues and adjacent normal tissues. Both loss‐ and gain‐of‐function assays were performed to examine the effects of PCAT1 and SOX2 on NSCLC cell behaviours in vivo and in vitro. Bioinformatic analyses, chromatin isolation by RNA purification (ChIRP) and dual‐luciferase reporter assays were applied to validate the regulatory effects of PCAT1 on SOX2 expression. Chromatin immunoprecipitation, luciferase and rescue assays were utilised to identify the relationship between SOX2 and the cGAS/stimulator of interferon genes (STING) signalling. PCAT1 was immunosuppressive and related with NSCLC invasion. Increased PCAT1 was negatively correlated with immune cell infiltration in NSCLC. PCAT1 knockdown restrained proliferation, increased apoptosis, and repressed cell metastasis in vivo and in vitro. PCAT1 activated SOX2 that accelerated tumorigenesis and immunosuppression. SOX2 promoted tumour growth through inhibiting cytotoxic T‐cell immunity. Moreover, SOX2 restrained cGAS transcription and hampered downstream type I interferon (IFN)‐induced immune responses. Inhibition of PCAT1/SOX2 in collaboration with radiation further inhibited tumour growth, and initiated the cGAS/STING signalling pathway, which enhanced the immune responses of radiotherapy in NSCLC. PCAT1/SOX2 axis promoted tumorigenesis and immunosuppression through inhibition of cGAS/STING signalling‐mediated T‐cell activation. Inhibition of PCAT1 and SOX2 synergised with radiotherapy to activate the immune response and could serve as potential therapeutic targets. LncRNA PCAT1 is highly expressed immunosuppressive in NSCLC via downregulating cGAS/STING signalling pathway. LncRNA PCAT1 upregulates SOX2 transcription and SOX2 downregulates cGAS transcription. LncRNA PCAT1 suppresses radioimmune responses through SOX2/cGAS/STING pathway and its downregulation increases the inhibitory effects of radiotherapy in NSCLC.
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DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1007/978-1-4939-6380-5_10
发表时间：
2016-01-01
期刊：
POLYCOMB GROUP PROTEINS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Chu, Ci;Chang, Howard Y.
通讯作者：
Chang, Howard Y.
影响因子：
3.7
作者：
Han, Xiaoyan;Na, Tao;Yuan, Bao-Zhu
通讯作者：
Yuan, Bao-Zhu
影响因子：
64.5
作者：
Lam KC;Araya RE;Huang A;Chen Q;Di Modica M;Rodrigues RR;Lopès A;Johnson SB;Schwarz B;Bohrnsen E;Cogdill AP;Bosio CM;Wargo JA;Lee MP;Goldszmid RS
通讯作者：
Goldszmid RS
DOI：
10.1164/rccm.201510-2084oc
发表时间：
2017-06-01
影响因子：
24.7
作者：
Correia, Lucia L.;Johnson, Jo-Anne;McCaughan, Frank M.
通讯作者：
McCaughan, Frank M.