环状 RNA circDLG1 通过海绵吸附 miR-141-3p 调控 CXCL12 促进胃癌进展和抗 PD-1 耐药。
The circular RNA circDLG1 promotes gastric cancer progression and anti-PD-1 resistance through the regulation of CXCL12 by sponging miR-141-3p.
机构信息
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-sen University Cancer Center, No. 651 Dong Feng East Road, Guangzhou, 510060, PR China.
Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, P. R. China.
出版信息
Mol Cancer. 2021 Dec 15;20(1):166. doi: 10.1186/s12943-021-01475-8.
BACKGROUND
Dysregulation of circular RNAs (circRNAs) plays an important role in the development of gastric cancer; thus, revealing the biological and molecular mechanisms of abnormally expressed circRNAs is critical for identifying novel therapeutic targets in gastric cancer.
METHODS
A circRNA microarray was performed to identify differentially expressed circRNAs between primary and distant metastatic tissues and between gastric cancer tissues sensitive or resistant to anti-programmed cell death 1 (PD-1) therapy. The expression of circRNA discs large homolog 1 (DLG1) was determined in a larger cohort of primary and distant metastatic gastric cancer tissues. The role of circDLG1 in gastric cancer progression was evaluated both in vivo and in vitro, and the effect of circDLG1 on the antitumor activity of anti-PD-1 was evaluated in vivo. The interaction between circDLG1 and miR-141-3p was assessed by RNA immunoprecipitation and luciferase assays.
RESULTS
circDLG1 was significantly upregulated in distant metastatic lesions and gastric cancer tissues resistant to anti-PD-1 therapy and was associated with an aggressive tumor phenotype and adverse prognosis in gastric cancer patients treated with anti-PD-1 therapy. Ectopic circDLG1 expression promoted the proliferation, migration, invasion, and immune evasion of gastric cancer cells. Mechanistically, circDLG1 interacted with miR-141-3p and acted as a miRNA sponge to increase the expression of CXCL12, which promoted gastric cancer progression and resistance to anti-PD-1-based therapy.
CONCLUSIONS
Overall, our findings demonstrate how circDLG1 promotes gastric cancer cell proliferation, migration, invasion and immune evasion and provide a new perspective on the role of circRNAs during gastric cancer progression.
背景
环状 RNA（circRNAs）的失调在胃癌的发展中起着重要作用；因此，揭示异常表达的 circRNAs 的生物学和分子机制对于确定胃癌的新治疗靶点至关重要。
方法
进行 circRNA 微阵列分析，以鉴定原发和远处转移组织以及对抗程序性细胞死亡 1（PD-1）治疗敏感或耐药的胃癌组织之间差异表达的 circRNAs。在更大的原发性和远处转移性胃癌组织队列中确定 circRNA 盘状结构域大同源物 1（DLG1）的表达。在体内和体外评估 circDLG1 在胃癌进展中的作用，并在体内评估 circDLG1 对抗 PD-1 治疗的抗肿瘤活性的影响。通过 RNA 免疫沉淀和荧光素酶测定评估 circDLG1 与 miR-141-3p 之间的相互作用。
结果
circDLG1 在远处转移病灶和抗 PD-1 治疗耐药的胃癌组织中显著上调，并与接受抗 PD-1 治疗的胃癌患者的侵袭性肿瘤表型和不良预后相关。外源性 circDLG1 表达促进了胃癌细胞的增殖、迁移、侵袭和免疫逃逸。机制上，circDLG1 与 miR-141-3p 相互作用，作为 miRNA 海绵增加 CXCL12 的表达，促进胃癌的进展和对基于抗 PD-1 的治疗的耐药性。
结论
总的来说，我们的研究结果表明 circDLG1 如何促进胃癌细胞的增殖、迁移、侵袭和免疫逃逸，并为 circRNAs 在胃癌进展过程中的作用提供了新的视角。
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