CircSCUBE3 Reduces the Anti-gastric Cancer Activity of Anti-PD-L1
HuSheng Shan1,2,3, XiaoBo Zhang1, Xiao Zhang1
1Department of Radiology, The First Medical Center, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China.
Abstract:
The progression of gastric cancer (GC) is closely related to tumor immune escape. The research, therefore, studied the impact of possible circRNAs on the immune escape of GC tumors and the underlying mechanisms. Here, to explore circRNAs that may affect GC, the differential circRNAs in six normal gastric mucosal tissues and six GC samples (GSM2005868-GSM2005879) were analyzed through the bioinformatics website circmine, and hsa_circ_0076092 (circSCUBE3) was identified as the research object. In vitro assays revealed the functions of circSCUBE3 and its downstream miRNA/mRNA axis in GC cells. The effect of circSCUBE3 against PD-1 anti-tumor activity was evaluated in vivo. The relationship between circSCUBE3 and miR-744-5p, miR-744-5p, and SLC7A5 was identified by RNA immunoprecipitation and dual-luciferase reporter experiments. The effect of SLC7A5 on GC immune escape by regulating PD-L1 expression was assessed by co-culture system and flow cytometry. CircSCUBE3 was up-regulated in human GC tissues and GC cell lines. circSCUBE3 was associated with poor prognosis in GC patients. Functional experiments reported that circSCUBE3 knockdown could suppress GC immune escape. Mechanistically, circSCUBE3 bound to miR-744-5p, which further targeted SLC7A5, and SLC7A5 can affect GC immune escape by regulating PD-L1. Furthermore, in vivo assay manifested that circSCUBE3 attenuated the anti-tumor effect of PD-L1. Our study revealed the importance of the circSCUBE3/miR-744-5p/SLC7A5 axis in GC immune escape and anti-PD-1 resistance.
Insights
This study identifies circSCUBE3 as a key player in gastric cancer immune escape. It reveals how circSCUBE3 promotes tumor progression and resistance to anti-PD-1 therapy by regulating the miR-744-5p/SLC7A5/PD-L1 axis.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Gastric cancer (GC) progression is linked to tumor immune escape.
- Circular RNAs (circRNAs) are increasingly recognized for their roles in cancer development.
- Understanding the mechanisms of GC immune escape is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of circRNAs in gastric cancer immune escape.
- To identify specific circRNAs affecting GC progression and their underlying molecular mechanisms.
- To explore the potential of targeting circRNAs for GC treatment.
Main Methods:
- Bioinformatic analysis of differential circRNAs in GC tissues.
- In vitro and in vivo assays to determine the function of circSCUBE3.
- RNA immunoprecipitation and dual-luciferase reporter assays to elucidate molecular interactions.
- Co-culture systems and flow cytometry to assess immune escape mechanisms.
Main Results:
- hsa_circ_0076092 (circSCUBE3) was identified as differentially expressed in GC.
- CircSCUBE3 is upregulated in GC tissues and associated with poor prognosis.
- CircSCUBE3 knockdown suppressed GC immune escape and attenuated anti-tumor effects of PD-1 therapy.
- The study identified the circSCUBE3/miR-744-5p/SLC7A5 axis regulating PD-L1 expression and GC immune escape.
Conclusions:
- CircSCUBE3 plays a significant role in promoting gastric cancer immune escape and anti-PD-1 resistance.
- The circSCUBE3/miR-744-5p/SLC7A5 axis is a critical pathway in GC immune evasion.
- CircSCUBE3 represents a potential therapeutic target for overcoming immune escape in gastric cancer.
