Abstract
Background: This study tried to explore the mechanism of long non-coding RNA (lncRNA) KCNQ1OT1 in tumor immune escape.Methods: Gene Expression Omnibus (GEO) and microarray analysis were used to screen the differentially expressed lncRNA and microRNA (miRNA) in normal tissues and tumor tissues. Quantitative reverse transcription PCR (RT-qPCR) was used to quantify KCNQ1OT1, miR-30a-5p, ubiquitin-specific peptidase 22 (USP22), and programmed death-ligand 1 (PD-L1). The interactive relationship between KCNQ1OT1 and miR-30a-5p was verified using dual-luciferase reporter gene assay and ribonucleoprotein immunoprecipitation (RIP) assay. Cell Counting Kit (CCK)-8, clone formation, wound healing, and apoptosis are used to detect the occurrence of tumor cells after different treatments. Protein half-life and ubiquitination detection are used to study the influence of USP22 on PD-L1 ubiquitination. BALB/c mice and BALB/c nude mice are used to detect the effects of different treatments on tumor growth and immune escape in vivo.Results: The expression of lncRNA KCNQ1OT1 in tumor tissues and tumor cell-derived exosomes was significantly increased. The tumor-promoting effect of lncRNA KCNQ1OT1 was through the autocrine effect of tumor cell-derived exosomes, which mediates the miR-30a-5p/USP22 pathway to regulate the ubiquitination of PD-L1 and inhibits CD8+ T-cell response, thereby promoting colorectal cancer development.Conclusion: Tumor cell-derived exosomes’ KCNQ1OT1 could regulate PD-L1 ubiquitination through miR-30a-5p/USP22 to promote colorectal cancer immune escape.
Highlights
Colorectal cancer (CRC) is one of the most common malignant tumors in the world
long non-coding RNA (LncRNA) KCNQ1OT1 Was Upregulated in Colorectal Cancer
We screened eight pairs of patients with different long non-coding RNA (lncRNA) in tumor tissues and adjacent tissues by Gene Expression Omnibus (GEO) analysis and found that KCNQ1OT1 was significantly higher in tumor tissues than that in adjacent tissues (Supplementary Figure 1A)
Summary
Colorectal cancer (CRC) is one of the most common malignant tumors in the world. In 2012, the number of global incidences exceeded 1.3 million with nearly 700,000 deaths (Chen X. et al, 2020). Recent studies have shown that the intrinsic functional expression of programmed death receptor 1 (PD-1) contributes to tumor immune resistance. PD-1 can be activated by the ligand programmed death-ligand 1 (PD-L1) expressed by tumor cells, regulate downstream mammalian rapamycin signaling targets, and promote tumor growth, regardless of adaptive immunity. According to reports, this PD-1 signal transduction has been found to promote cancer in liver cancer cells, bladder cancer, and non-small-cell lung cancer cells (Kleffel et al, 2015; Li et al, 2017; Yao et al, 2018). This study tried to explore the mechanism of long non-coding RNA (lncRNA) KCNQ1OT1 in tumor immune escape
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