Division of Gastric Surgery, Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China.
Department of General Surgery, The Second Affiliated Hospital of Nantong university, Nantong, 226001, Jiangsu Province, People's Republic of China.
Mol Cancer. 2021 Apr 9;20(1):66. doi: 10.1186/s12943-021-01358-y.
A novel type of noncoding RNA, circRNA has been reported to participate in the occurrence and development of diseases through many mechanisms. The MAPK pathway is a common signal transduction pathway involved in cell proliferation, inflammation and apoptosis and plays a particularly important role in cancers. However, the role of circRNAs related to the MAPK pathway in gastric cancer has not been explored.
A bioinformatics analysis was performed to profile and identify the circRNAs involved in the MAPK pathway in gastric cancer. The tumor-suppressive role of circMAPK1 was confirmed both in vitro and in vivo. Mass spectrometry, Western blot and immunofluorescence staining assays were used to validate the existence and expression of MAPK1-109aa. The molecular mechanism of circMAPK1 was investigated by mass spectrometry and immunoprecipitation analyses.
In this study, we identified that circMAPK1 (hsa_circ_0004872) was downregulated in gastric cancer tissues compared with adjacent normal tissues. Importantly, lower circMAPK1 expression predicted poor survival in GC patients. CircMAPK1 inhibited the proliferation and invasion of gastric cancer cells in vitro and in vivo. Next, we found that circMAPK1 encoded a novel protein with 109 amino acids in length. Through a series of functional experiments, we confirmed that circMAPK1 exerted a tumor-suppressing effect via the encoded protein MAPK1-109aa. Mechanistically, the tumor suppressor MAPK1-109aa inhibited the phosphorylation of MAPK1 by competitively binding to MEK1, thereby suppressing the activation of MAPK1 and its downstream factors in MAPK pathway.
Our study revealed that circMAPK1 inhibits the malignant biological behavior of gastric cancer cells through its encoded protein MAPK1-109aa. More importantly, circMAPK1 is a favorable predictor for gastric cancer patients and may provide a new therapeutic target in the treatment of gastric cancer.
一种新型的非编码 RNA，circRNA 已被报道通过多种机制参与疾病的发生和发展。MAPK 途径是一种参与细胞增殖、炎症和凋亡的常见信号转导途径，在癌症中起着尤为重要的作用。然而，与 MAPK 途径相关的 circRNAs 在胃癌中的作用尚未被探索。
通过生物信息学分析，对胃癌中涉及 MAPK 途径的 circRNAs 进行了分析和鉴定。在体外和体内证实了 circMAPK1 的肿瘤抑制作用。质谱分析、Western blot 和免疫荧光染色实验用于验证 MAPK1-109aa 的存在和表达。通过质谱分析和免疫沉淀分析研究了 circMAPK1 的分子机制。
本研究发现，与相邻正常组织相比，circMAPK1（hsa_circ_0004872）在胃癌组织中表达下调。重要的是，circMAPK1 表达水平较低预示着 GC 患者的生存预后较差。circMAPK1 在体外和体内抑制了胃癌细胞的增殖和侵袭。接下来，我们发现 circMAPK1 编码一个具有 109 个氨基酸长度的新型蛋白质。通过一系列功能实验，我们证实 circMAPK1 通过编码的蛋白 MAPK1-109aa 发挥肿瘤抑制作用。机制上，肿瘤抑制因子 MAPK1-109aa 通过竞争性结合 MEK1 抑制 MAPK1 的磷酸化，从而抑制 MAPK 途径中 MAPK1 及其下游因子的激活。
我们的研究表明，circMAPK1 通过其编码蛋白 MAPK1-109aa 抑制胃癌细胞的恶性生物学行为。更重要的是，circMAPK1 是胃癌患者的有利预后指标，可能为胃癌的治疗提供新的治疗靶点。
