The A-to-I editing of KPC1 promotes intrahepatic cholangiocarcinoma by attenuating proteasomal processing of NF-κB1 p105 to p50.
The A-to-I editing of KPC1 promotes intrahepatic cholangiocarcinoma by attenuating proteasomal processing of NF-κB1 p105 to p50.
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DOI：
10.1186/s13046-022-02549-1
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发表时间：
2022-12-08
影响因子：
11.3
通讯作者：
Zhou, Gangqiao
中科院分区：
文献类型：
--
作者：
Gao, Chengming;Zhou, Guangming;Shi, Jie;Shi, Peipei;Jin, Liang;Li, Yuanfeng;Wang, Xiaowen;Liao, Song;Yan, Han;Wu, Junjie;Lu, Yiming;Zhai, Yun;Zhang, Jinxu;Zhang, Haitao;Zhang, Hongxing;Yang, Chenning;Cao, Pengbo;Cheng, Shuqun;Zhou, Gangqiao
腺苷到肌苷（A-to-I）的异常RNA编辑与多种人类癌症有关，但其在肝内胆管癌（iCCA）中的作用仍然未知。我们进行了一项外显子组范围的研究，以寻找驱动iCCA发病机制的失调RNA编辑。进行整合的全外显子组和转录组测序分析以阐明iCCA中的RNA编辑景观。通过桑格测序验证推定的RNA编辑位点。体外和体内实验用于评估示例性靶基因Kip 1泛素化促进复合物1（KPC 1）及其编辑对iCCA细胞生长和转移的影响。通过分子生物学方法分析KPC 1 RNA编辑与NF-κB信号转导之间的串扰。通过整合组学分析，我们揭示了一种腺苷脱氨酶作用于RNA 1A（ADAR 1）介导的iCCA中的过度编辑模式。ADAR 1在iCCAs中经常扩增和过表达，并发挥致癌作用。值得注意的是，我们确定了一种新的ADAR 1介导的A-to-I编辑KPC 1转录本，这导致在第8位残基（p.M8V）处蛋氨酸被缬氨酸取代。KPC 1 p.M8V编辑通过钝化野生型KPC 1的肿瘤抑制作用赋予功能丧失表型。从机制上讲，KPC 1 p.M8V减弱了KPC 1对其底物NF-κB1 p105的亲和力，从而减少了p105至p50的泛素化和蛋白酶体加工，这反过来又增强了致癌NF-κB信号传导的活性。我们的研究结果表明，扩增驱动的ADAR 1过表达导致iCCA中KPC 1 p.M8V的减少，通过激活NF-κB信号通路导致进展，并建议ADAR 1-KPC 1-NF-κB轴作为iCCA的潜在治疗靶点。在线版本包含补充材料，可通过10.1186/s13046-022-02549-1获得。
Aberrant RNA editing of adenosine-to-inosine (A-to-I) has been linked to multiple human cancers, but its role in intrahepatic cholangiocarcinoma (iCCA) remains unknown. We conducted an exome-wide investigation to search for dysregulated RNA editing that drive iCCA pathogenesis. An integrative whole-exome and transcriptome sequencing analysis was performed to elucidate the RNA editing landscape in iCCAs. Putative RNA editing sites were validated by Sanger sequencing. In vitro and in vivo experiments were used to assess the effects of an exemplary target gene Kip1 ubiquitination-promoting complex 1 (KPC1) and its editing on iCCA cells growth and metastasis. Crosstalk between KPC1 RNA editing and NF-κB signaling was analyzed by molecular methods. Through integrative omics analyses, we revealed an adenosine deaminases acting on RNA 1A (ADAR1)-mediated over-editing pattern in iCCAs. ADAR1 is frequently amplified and overexpressed in iCCAs and plays oncogenic roles. Notably, we identified a novel ADAR1-mediated A-to-I editing of KPC1 transcript, which results in substitution of methionine with valine at residue 8 (p.M8V). KPC1 p.M8V editing confers loss-of-function phenotypes through blunting the tumor-suppressive role of wild-type KPC1. Mechanistically, KPC1 p.M8V weakens the affinity of KPC1 to its substrate NF-κB1 p105, thereby reducing the ubiquitinating and proteasomal processing of p105 to p50, which in turn enhances the activity of oncogenic NF-κB signaling. Our findings established that amplification-driven ADAR1 overexpression results in overediting of KPC1 p.M8V in iCCAs, leading to progression via activation of the NF-κB signaling pathway, and suggested ADAR1-KPC1-NF-κB axis as a potential therapeutic target for iCCA. The online version contains supplementary material available at 10.1186/s13046-022-02549-1.
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影响因子：
29.4
作者：
Ilyas SI;Gores GJ
通讯作者：
Gores GJ
影响因子：
24.5
作者：
Chan TH;Lin CH;Qi L;Fei J;Li Y;Yong KJ;Liu M;Song Y;Chow RK;Ng VH;Yuan YF;Tenen DG;Guan XY;Chen L
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Chen L
影响因子：
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作者：
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通讯作者：
Bass, Brenda L.
影响因子：
5.8
作者：
Carr, I. M.;Robinson, J. I.;Bonthron, D. T.
通讯作者：
Bonthron, D. T.
影响因子：
15.3
作者：
Han, Sae-Won;Kim, Hwang-Phill;Kim, Tae-You
通讯作者：
Kim, Tae-You