Prinz Christian, Weber David
Lehrstuhl für Innere Medizin1, University of Witten gGmbH, Helios Universitätsklinikum, D-42283 Wuppertal, Germany.
Oncotarget. 2020 Mar 10;11(10):894-904. doi: 10.18632/oncotarget.27520.
Dysregulation of noncoding microRNA molecules has been associated with immune cell activation in the context of induced gastric inflammation as well as carcinogenesis, but also with downregulation of mismatch repair genes, and may interfere with immune checkpoint proteins that lead to the overexpression of antigens on gastric tumor cells. Numerous miR-molecules have been described as important tools and markers in gastric inflammation and cancer development -including miR-21, miR-143, miR-145, miR-201, and miR-335- all of which are downregulated in gastric tumors, and involved in cell cycle growth or tumor invasion. Among the many microRNAs involved in gastric inflammation, adenocarcinoma development and immune checkpoint regulation, miR-155 is notable in that its upregulation is considered a key marker of chronic gastric inflammation that predisposes a patient to gastric carcinogenesis. Among various other miRs, miR-155 is highly expressed in activated B and T cells and in monocytes/macrophages present in chronic gastric inflammation. Notably, miR-155 was shown to downregulate the expression of certain MMR genes, such as MLH1, MSH2, and MSH6. In tumor-infiltrating miR-155-deficient CD8 T cells, antibodies against immune checkpoint proteins restored the expression of several derepressed miR-155 targets, suggesting that miR-155 may regulate overlapping pathways to promote antitumor immunity. It may thus be of high clinical impact that gastric pathologies mediated by miR-155 result from its overexpression. This suggests that it may be possible to therapeutically attenuate miR-155 levels for gastric cancer treatment and/or to prevent the progression of chronic gastric inflammation into cancer.
在诱导性胃炎以及致癌过程中，非编码微小RNA分子的失调不仅与免疫细胞激活有关，还与错配修复基因的下调有关，并且可能干扰免疫检查点蛋白，导致胃肿瘤细胞上抗原的过度表达。许多miR分子已被描述为胃炎和癌症发展中的重要工具和标志物，包括miR-21、miR-143、miR-145、miR-201和miR-335，所有这些在胃肿瘤中均下调，并参与细胞周期生长或肿瘤侵袭。在参与胃炎、腺癌发展和免疫检查点调节的众多微小RNA中，miR-155值得注意，因为其上调被认为是慢性胃炎的关键标志物，使患者易患胃癌。在各种其他miR中，miR-155在活化的B细胞和T细胞以及慢性胃炎中的单核细胞/巨噬细胞中高度表达。值得注意的是，miR-155被证明可下调某些错配修复基因的表达，如MLH1、MSH2和MSH6。在肿瘤浸润的miR-155缺陷型CD8 T细胞中，针对免疫检查点蛋白的抗体恢复了几个被抑制的miR-155靶标的表达，表明miR-155可能调节重叠途径以促进抗肿瘤免疫。因此，由miR-155介导的胃部病变因其过表达而产生，这可能具有很高的临床意义。这表明，有可能通过治疗降低miR-155水平来治疗胃癌和/或预防慢性胃炎发展为癌症。
