Immunosuppressive lncRNA LINC00624 promotes tumor progression and therapy resistance through ADAR1 stabilization.
Immunosuppressive lncRNA LINC00624 promotes tumor progression and therapy resistance through ADAR1 stabilization.
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免疫抑制性 lncRNA LINC00624 通过 ADAR1 稳定促进肿瘤进展和治疗耐药
DOI：
10.1136/jitc-2022-004666
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发表时间：
2022-10
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
--
作者：
背景尽管HER 2靶向治疗成功延长了约50%接受治疗的患者的生存期，但治疗耐药性仍然是HER 2+乳腺癌（BC）患者面临的一个重要挑战。适应性和先天性免疫应答对HER 2 +BC患者治疗结果的影响已得到广泛证实。方法采用RNA-seq技术筛选HER 2阳性非病理性完全缓解（pCR）乳腺癌中表达的长链非编码RNA。生存分析采用Kaplan-Meier法。进行细胞死亡测定和增殖测定以确认LINC 00624的表型。RT-qPCR和western blot用于测定IFN应答。异种移植小鼠模型用于体内确认抗neu治疗抗性。RNA pull-down和免疫印迹用于确认ADAR 1和LINC 00624的相互作用。从杆状病毒表达系统中纯化ADAR 1重组蛋白。B16-OVA细胞用于研究体外和体内的抗原呈递。采用流式细胞术检测移植瘤免疫细胞浸润情况。反义寡核苷酸（ASO）用于体内治疗。结果LINC 00624通过抑制I型干扰素（IFN）通路的激活，在体内外阻断HER 2靶向治疗的抗肿瘤效应。LINC 00624的双链RNA样结构可以结合并被腺苷（A）编辑至肌苷（I）RNA编辑酶腺苷脱氨酶RNA特异性1（ADAR 1），并且这种编辑已经显示释放生长抑制并减弱由IFN应答引起的先天免疫应答。值得注意的是，LINC 00624通过抑制由β-TrCP触发的ADAR 1的泛素化诱导的降解来促进ADAR 1的稳定。相比之下，LINC 00624抑制主要组织相容性复合体（MHC）I类抗原呈递，并限制癌症微环境中的CD 8 +T细胞浸润，导致免疫检查点阻断抑制和通过ADAR 1介导的抗HER 2治疗抗性。结论LINC 00624是一种肿瘤免疫抑制性lncRNA，通过反义寡核苷酸靶向LINC 00624在高表达LINC 00624的肿瘤中具有巨大的临床应用潜力。
Background Despite the success of HER2-targeted therapy in achieving prolonged survival in approximately 50% of treated individuals, treatment resistance is still an important challenge for HER2+ breast cancer (BC) patients. The influence of both adaptive and innate immune responses on the therapeutic outcomes of HER2+BC patients has been extensively demonstrated. Methods Long non-coding RNAs expressed in non-pathological complete response (pCR) HER2 positive BC were screened and validated by RNA-seq. Survival analysis were made by Kaplan-Meier method. Cell death assay and proliferation assay were performed to confirm the phenotype of LINC00624. RT-qPCR and western blot were used to assay the IFN response. Xenograft mouse model were used for in vivo confirmation of anti-neu treatment resistance. RNA pull-down and immunoblot were used to confirm the interaction of ADAR1 and LINC00624. ADAR1 recombinant protein were purified from baculovirus expression system. B16-OVA cells were used to study antigen presentation both in vitro and in vivo. Flow cytometry was used to determine the tumor infiltrated immune cells of xenograft model. Antisense oligonucleotides (ASOs) were used for in vivo treatment. Results In this study, we found that LINC00624 blocked the antitumor effect of HER2- targeted therapy both in vitro and in vivo by inhibiting type I interferon (IFN) pathway activation. The double-stranded RNA-like structure of LINC00624 can bind and be edited by the adenosine (A) to inosine (I) RNA-editing enzyme adenosine deaminase RNA specific 1 (ADAR1), and this editing has been shown to release the growth inhibition and attenuate the innate immune response caused by the IFN response. Notably, LINC00624 promoted the stabilization of ADAR1 by inhibiting its ubiquitination-induced degradation triggered by β-TrCP. In contrast, LINC00624 inhibited major histocompatibility complex (MHC) class I antigen presentation and limited CD8+T cell infiltration in the cancer microenvironment, resulting in immune checkpoint blockade inhibition and anti-HER2 treatment resistance mediated through ADAR1. Conclusions In summary, these results suggest that LINC00624 is a cancer immunosuppressive lncRNA and targeting LINC00624 through ASOs in tumors expressing high levels of LINC00624 has great therapeutic potential in future clinical applications.
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影响因子：
11.2
作者：
Herrmann, F;Lehr, HA;Seliger, B
通讯作者：
Seliger, B
影响因子：
14.9
作者：
Fritzell, Kajsa;Xu, Li-Di;Ohman, Marie
通讯作者：
Ohman, Marie
DOI：
10.1016/s1470-2045(16)30631-3
发表时间：
2017-01
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Luen SJ;Salgado R;Fox S;Savas P;Eng-Wong J;Clark E;Kiermaier A;Swain SM;Baselga J;Michiels S;Loi S
通讯作者：
Loi S
DOI：
10.1093/bioinformatics/btr209
发表时间：
2011-07-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Lin MF;Jungreis I;Kellis M
通讯作者：
Kellis M
影响因子：
12.3
作者：
Jansz N;Faulkner GJ
通讯作者：
Faulkner GJ