Circular RNA circMET drives immunosuppression and anti-PD1 therapy resistance in hepatocellular carcinoma via the miR-30-5p/snail/DPP4 axis
Circular RNA circMET drives immunosuppression and anti-PD1 therapy resistance in hepatocellular carcinoma via the miR-30-5p/snail/DPP4 axis
复制标题
环状 RNA circMET 通过 miR-30-5p/snail/DPP4 轴驱动肝细胞癌的免疫抑制和抗 PD1 治疗耐药性。
DOI：
10.1186/s12943-020-01213-6
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发表时间：
2020-05-19
期刊：
影响因子：
37.3
通讯作者：
Shi, Guo-Ming
中科院分区：
文献类型：
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作者：
Huang, Xiao-Yong;Zhang, Peng-Fei;Shi, Guo-Ming
染色体7 q21 - 7 q31的扩增与肿瘤复发和多药耐药相关，该区域的几个基因是肝细胞癌（HCC）的强有力驱动因素。我们的目的是研究该区域中调节HCC发生和发展的关键环状RNA（circRNA）。方法采用qRT-PCR技术检测43个circRNA在人肝癌组织和癌旁组织中的表达。此外，我们使用培养的HCC细胞来修饰circRNA表达，并在几种基于细胞的测定以及通过RNA-seq的基因表达分析中评估了效果。将修饰的细胞植入免疫活性小鼠以评估对肿瘤发展的影响。我们进行了额外的实验，以确定这些影响的作用机制。结果circMET（hsa_circ_0082002）在肝癌组织中高表达，circMET表达与肝癌患者的生存和复发有关。通过体外修饰肝癌细胞中circMET的表达，我们发现circMET过表达通过诱导上皮细胞向间充质细胞转化并增强免疫抑制性肿瘤微环境来促进肝癌的发展。从机制上讲，circMET通过miR-30- 5 p/Snail/二肽基肽酶4（DPP 4）/CXCL 10轴诱导这种微环境。此外，DPP 4抑制剂西他列汀和抗PD 1抗体的组合改善了免疫活性小鼠的抗肿瘤免疫力。临床上，接受西格列汀治疗的糖尿病患者的HCC组织显示出比未接受西格列汀治疗的糖尿病HCC患者更高的CD 8（+）T细胞浸润。结论circMET是通过Snail/DPP 4/CXCL 10轴诱导HCC发展和免疫耐受的癌-circRNA。此外，西格列汀可能增强抗PD 1治疗在HCC患者亚组中的疗效。
Background Amplification of chromosome 7q21-7q31 is associated with tumor recurrence and multidrug resistance, and several genes in this region are powerful drivers of hepatocellular carcinoma (HCC). We aimed to investigate the key circular RNAs (circRNAs) in this region that regulate the initiation and development of HCC. Methods We used qRT-PCR to assess the expression of 43 putative circRNAs in this chromosomal region in human HCC and matched nontumor tissues. In addition, we used cultured HCC cells to modify circRNA expression and assessed the effects in several cell-based assays as well as gene expression analyses via RNA-seq. Modified cells were implanted into immunocompetent mice to assess the effects on tumor development. We performed additional experiments to determine the mechanism of action of these effects. Results circMET (hsa_circ_0082002) was overexpressed in HCC tumors, and circMET expression was associated with survival and recurrence in HCC patients. By modifying the expression of circMET in HCC cells in vitro, we found that circMET overexpression promoted HCC development by inducing an epithelial to mesenchymal transition and enhancing the immunosuppressive tumor microenvironment. Mechanistically, circMET induced this microenvironment through the miR-30-5p/Snail/ dipeptidyl peptidase 4(DPP4)/CXCL10 axis. In addition, the combination of the DPP4 inhibitor sitagliptin and anti-PD1 antibody improved antitumor immunity in immunocompetent mice. Clinically, HCC tissues from diabetic patients receiving sitagliptin showed higher CD8(+) T cell infiltration than those from HCC patients with diabetes without sitagliptin treatment. Conclusions circMET is an onco-circRNA that induces HCC development and immune tolerance via the Snail/DPP4/CXCL10 axis. Furthermore, sitagliptin may enhance the efficacy of anti-PD1 therapy in a subgroup of patients with HCC.