Targeting HNRNPM Inhibits Cancer Stemness and Enhances Antitumor Immunity in Wnt-activated Hepatocellular Carcinoma.
Targeting HNRNPM Inhibits Cancer Stemness and Enhances Antitumor Immunity in Wnt-activated Hepatocellular Carcinoma.
复制标题
靶向 HNRNPM 可抑制 Wnt 激活的肝细胞癌的癌症干细胞性并增强抗肿瘤免疫。
DOI：
10.1016/j.jcmgh.2022.02.006
复制
发表时间：
2022
影响因子：
7.2
通讯作者：
Dai Z
中科院分区：
文献类型：
--
作者：
Zhu GQ;Wang Y;Wang B;Liu WR;Dong SS;Chen EB;Cai JL;Wan JL;Du JX;Song LN;Chen SP;Yu L;Zhou ZJ;Wang Z;Zhou J;Shi YH;Fan J;Dai Z
肿瘤干细胞和免疫逃避密切相关，在肿瘤的发展和免疫治疗的抵抗中起着关键作用。然而，对协调这种关联的潜在分子机制知之甚少。分析了240例肝细胞癌（HCC）样本、公共数据库和肝脏发育数据库中异质核核糖核蛋白M （HNRNPM）的表达情况。采用染色质免疫沉淀法探讨干细胞转录因子与HNRNPM之间的关系。通过RNA-seq和RIP-seq鉴定了hnrnpm调控的选择性剪接（AS）及其结合基序。hnrnpm特异性的反义寡核苷酸被开发用于探索HCC的潜在治疗靶点。流式细胞术对与肿瘤细胞共培养的CD8+ T细胞进行分选。我们在HCC中发现了一个升高的癌胎剪接因子HNRNPM，它统一并调节了癌症干细胞和免疫逃避之间的正相关。HNRNPM敲除可在体外和体内消除HCC的肿瘤发生并降低癌症干细胞的特性。从机制上讲，HNRNPM通过结合MBD2的侧翼内含子来调节其AS，其同工异构体发挥相反的作用。虽然MBD2a和MBD2c竞争性地结合FZD3启动子中的CpG岛，但MBD2a优先增加FZD3的表达，进而激活WNT/β-catenin通路。有趣的是，FZD3和β-catenin通过靶向OCT4和SOX2进一步提供了额外的调控。我们发现HNRNPM抑制显著促进CD8+ T细胞活化，HNRNPM-反义寡核苷酸有效抑制WNT/β-catenin通过促进CD8+ T细胞浸润来增强抗程序性细胞死亡蛋白-1免疫治疗。HNRNPM在通过as依赖机制产生免疫抑制HCC环境方面具有肿瘤固有功能，并证明了靶向HNRNPM在定制HCC免疫治疗方法中的概念。
Cancer stemness and immune evasion are closely associated and play critical roles in tumor development and resistance to immunotherapy. However, little is known about the underlying molecular mechanisms that coordinate this association. The expressions of heterogeneous nuclear ribonucleoprotein M (HNRNPM) in 240 hepatocellular carcinoma (HCC) samples, public databases, and liver development databases were analyzed. Chromatin immunoprecipitation assays were performed to explore the associations between stem-cell transcription factors and HNRNPM. HNRNPM-regulated alternative splicing (AS) and its binding motif were identified by RNA-seq and RIP-seq. HNRNPM-specific antisense oligonucleotides were developed to explore potential therapeutic targets in HCC. CD8+ T cells that were co-cultured with tumor cells were sorted by flow cytometry assays. We identified an elevated oncofetal splicing factor in HCC, HNRNPM, that unifies and regulates the positive association between cancer stemness and immune evasion. HNRNPM knockdown abolished HCC tumorigenesis and diminished cancer stem cell properties in vitro and in vivo. Mechanistically, HNRNPM regulated the AS of MBD2 by binding its flanking introns, whose isoforms played opposing roles. Although MBD2a and MBD2c competitively bound to CpG islands in the FZD3 promoter, MBD2a preferentially increased FZD3 expression and then activated the WNT/β-catenin pathway. Interestingly, FZD3 and β-catenin further provided additional regulation by targeting OCT4 and SOX2. We found that HNRNPM inhibition significantly promoted CD8+ T cell activation and that HNRNPM- antisense oligonucleotides effectively inhibited WNT/β-catenin to enhance anti-programmed cell death protein-1 immunotherapy by promoting CD8+ T cell infiltration. HNRNPM has a tumor-intrinsic function in generating an immunosuppressive HCC environment through an AS-dependent mechanism and demonstrates proof of the concept of targeting HNRNPM in tailoring HCC immunotherapeutic approaches.
登录
查看更多内容
影响因子：
5.3
作者：
Li H;Liu J;Shen S;Dai D;Cheng S;Dong X;Sun L;Guo X
通讯作者：
Guo X
影响因子：
23.9
作者：
Lu, Yu;Loh, Yuin-Han;Li, Hu;Cesana, Marcella;Ficarro, Scott B.;Parikh, Jignesh R.;Salomonis, Nathan;Toh, Cheng-Xu Delon;Andreadis, Stelios T.;Luckey, C. John;Collins, James J.;Daley, George Q.;Marto, Jarrod A.
通讯作者：
Marto, Jarrod A.
DOI：
10.1073/pnas.1813802116
发表时间：
2019-03-05
影响因子：
11.1
作者：
Li, Chen;Nguyen, Vincent;Boiko, Alexander D.
通讯作者：
Boiko, Alexander D.
影响因子：
3.2
作者：
Mei, Lin;Xiong, Wen-Cheng
通讯作者：
Xiong, Wen-Cheng
影响因子：
5.1
作者：
Low YH;Asi Y;Foti SC;Lashley T
通讯作者：
Lashley T