Abstract
BackgroundDysregulation 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.MethodsA 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.ResultscircDLG1 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.ConclusionsOverall, 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.
Highlights
Dysregulation of circular RNAs plays an important role in the development of gastric cancer; revealing the biological and molecular mechanisms of abnormally expressed Circular RNA (circRNA) is critical for identifying novel therapeutic targets in gastric cancer
Kaplan–Meier analysis showed that circDLG1 expression was significantly associated with progression-free survival (PFS) in gastric cancer patients treated with anti-programmed death-1 (PD-1) therapy, and patients with low circDLG1 expression presented with significantly better prognosis than those with (See figure on page.) Fig. 1 Identification of gastric cancer progression- and immune evasion-associated circRNAs through microarray. a A circRNA microarray was performed to identify differentially expressed circRNAs in gastric cancer tissues
The circus plot shows the distribution and expression profiles of the detected and differentially expressed circRNAs located on human chromosomes, as well as potential miRNAs interacting with differentially expressed circRNAs. b The heatmap presents the significantly expressed circRNAs in primary and paired distant metastatic gastric cancer tissues (n = 9). c The heatmap presents the significantly expressed circRNAs in primary gastric cancer tissues responsive (n = 3) or resistant (n = 4) to anti-progressive disease (PD)-1 therapy. d Relative expression of circDLG1 in primary and distant metastatic gastric cancer tissues measured by qRT–PCR (n = 30) (P < 0.001)
Summary
Dysregulation of circular RNAs (circRNAs) plays an important role in the development of gastric cancer; revealing the biological and molecular mechanisms of abnormally expressed circRNAs is critical for identifying novel therapeutic targets in gastric cancer. In recent years, increasing evidence has shown that immune evasion is essential for tumor survival and development [2, 3]. PD-L1 has been proven to be a predictive biomarker of anti-PD-1 efficacy in several tumor types. The KENOTE-061 and KENOTE-062 trials showed better survival in patients with PD-L1-positive tumors after pembrolizumab treatment [11, 12]. Data from the Checkmate, JAVELIN Gastric 300, and ATTRCTION-2 trials did not support the concept of PD-L1 positivity as a predictive biomarker of anti-PD-1 efficacy [13,14,15]. A better understanding of the molecular mechanisms that contribute to gastric cancer progression and immune evasion is critical for developing effective therapeutic strategies for this disease
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