Journal Article

The circular RNA circDLG1 promotes gastric cancer progression and anti-PD-1 resistance through the regulation of CXCL12 by sponging miR-141-3p

Sheng, Hui, Chen, Dong-Liang, Song, Kang, Xu, Rui-Hua, Zhao, Bai-Tian, Zhang, Dong-Sheng, Jin, Ying, Chen, Nuo

2021

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animals / Antibodies / Antitumor activity / Apoptosis / Biomarkers / Biomedical and Life Sciences / Biomedicine / Biopsy / Bladder cancer / Cancer / Cancer Research / Cancer therapies / Cell cycle / Cell death / Cell growth / Cell Line, Tumor / Cell migration / Cell proliferation / Chemokine CXCL12 - genetics / circDLG1 / Circular RNA / Colorectal cancer / CXCL12 protein / Development and progression / Discs Large Homolog 1 Protein - genetics / Disease Models, Animal / Disease Progression / Drug Resistance, Neoplasm / Gastric cancer / Gene expression / Gene Expression Regulation, Neoplastic / Gene Knockdown Techniques / Health aspects / Humans / Immune Checkpoint Inhibitors / Immune evasion / Immunoprecipitation / Invasion / Ligands / Lymphocytes / Medical prognosis / Metastases / Metastasis / Mice / MicroRNAs - genetics / miRNA / Molecular modelling / Oncology / PD-1 protein / Phenotypes / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Proliferation / Proteins / Response rates / RNA / RNA Interference / RNA, Circular / Stomach cancer / Stomach Neoplasms - genetics / Stomach Neoplasms - metabolism / Stomach Neoplasms - mortality / Stomach Neoplasms - pathology / Therapeutic targets / Tumor Escape / Tumors / Xenograft Model Antitumor Assays