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

Abstract

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.

Emerging roles of circular RNAs in gastric cancer metastasis and drug resistance

“…Anti-programmed cell death protein 1 (PD-1) monoclonal antibody is a commonly used immune-checkpoint blockade agent for GC immunotherapy [ 116 ]. The circRNA circDLG1 facilitates GC progression and anti-PD-1 resistance via miR-141-3p -mediated the regulation of CXCL12 [ 106 ].…”

“…Considering that circRNAs possess unique features such as tissue-and developmental stage-specific patterns, structural resistance to exonucleases and longer halflives, and specific circRNAs play essential roles in GC metastasis and drug resistance, manipulating circRNA abundance appears to be a promising therapeutic strategy for the advanced GC treatment [126-128, 131, 132]. Furthermore, combining circRNAs-based therapeutic interventions with traditional chemotherapy or targeted therapy offers a unique opportunity to conquer drug resistance in advanced GC patients [97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][113][114][115][116][117]. However, choosing crucial target circRNAs of interest is still a problem.…”

Optimization of Cas9 RNA sequence to reduce its unexpected effects as a microRNA sponge

“…To analyze the regulatory effect of Cas9 on its predicted binding microRNAs and their target genes, we first mined a database with the transcriptome characteristics of 331 cell lines overexpressing a Cas9 RNA and their parental control counterparts [12]. We also analyzed the binding possibilities between this Cas9 RNA and all the known human miRNAs using miRanda software [8]. The 51 miRNAs that were predicted to have the highest likelihood of binding Cas9 RNA were named "Cas9-miRNAs" (Fig.…”

“…A wide range of interactions between microRNAs (miRNAs) and mRNAs occur, not only in the 3′ untranslated regions but also in the amino acid coding sequences (CDSs) of mRNA [5,6]. An increasing number of research groups [7,8], including our team [9][10][11], recently found that a long RNA can bind and adsorb partially complementary miRNAs through a "miRNA sponge" mechanism, upregulating other target genes inhibited by these miRNAs. In this study, we investigated whether Cas9 RNA, an exogenous long-chain nucleic acid substance, could affect host cell gene expression through a miRNA sponge mechanism and developed an RNA sequence optimization strategy to improve the safety of this gene-editing system.…”

Establishment of a circular RNA regulatory stemness-related gene pair signature for predicting prognosis and therapeutic response in colorectal cancer

“…CircIL4R competes with miR-761 to upregulate TRIM29 expression and promote CRC progression ( 6 ). In gastric cancer, high expression levels of circDLG1 were correlated with poor prognosis in immunotherapy-treated patients and promoted the migration, invasion, and immune escape of gastric cancer cells ( 7 ). Cancer stem cells (CSCs) are considered to underlie tumorigenesis, metastasis, and recurrence and have the characteristics of self-renewal and differentiation potential ( 8 ).…”