LncRNA KCNQ1OT1 Secreted by Tumor Cell-Derived Exosomes Mediates Immune Escape in Colorectal Cancer by Regulating PD-L1 Ubiquitination via MiR-30a-5p/USP22

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.

The Role of Cancer Stem Cell-Derived Exosomes in Cancer Progression

“…Exosomes derived from pancreatic cancer (PaCa) cells had high levels of miR-212-3p, which inhibited the expression of regulatory factor X-associated protein (RFXAP), resulting in a decrease in the expression of MHC II molecules and inducing immune tolerance [ 50 ]. Xian et al found that the tumor-promoting effect of the lncRNA KCNQ1OT1 occurred through autocrine effects of colorectal cancer cell-derived exosomes (CRC-Exos), which mediated the miR-30a-5p/USP22 pathway to regulate the ubiquitination of PD-L1 and inhibit the CD8+ T-cell response, thereby promoting colorectal cancer development [ 51 ]. Growing evidence links tumor progression with the activity of various immune cells, such as macrophages.…”

Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers

“…Additionally, KCNQ1OT1 expression is upmodulated in methotrexate-resistant colorectal cancer cells, and KCNQ1OT1 silencing re-sensitizes resistant cells to methotrexate through downregulating cAMP-response element binding protein (CREB) and CREB-binding protein (CBP) levels [146]. Of late, KCNQ1OT1 was observed to support ubiquitin-specific peptidase 22 (USP22)-mediated stabilization of PD-L1 by deactivating miR-30a-5p and thereby inhibiting the anti-cancer immunity of CD8+ T cells [127]. Since KCNQ1OT1 is secreted from cancer cells via exosomes, the reciprocal transfer of KCNQ1OT1 between cancer cells can substantially increase PD-L1 levels, contributing to immune evasion [127] (Figure 4 and Table 2).…”

“…Of late, KCNQ1OT1 was observed to support ubiquitin-specific peptidase 22 (USP22)-mediated stabilization of PD-L1 by deactivating miR-30a-5p and thereby inhibiting the anti-cancer immunity of CD8+ T cells [127]. Since KCNQ1OT1 is secreted from cancer cells via exosomes, the reciprocal transfer of KCNQ1OT1 between cancer cells can substantially increase PD-L1 levels, contributing to immune evasion [127] (Figure 4 and Table 2). KCNQ1OT1 knockdown may activate other oncogenic factors, since miR-30a-5p is intriguingly capable of negatively regulating tumor-suppressive genes [147,148].…”

Potential Biological Roles of Exosomal Long Non-Coding RNAs in Gastrointestinal Cancer

“…Xian’s group found that lncRNA KCNQ1OT1 derived from CRC cells can promote CRC progression. Mechanistically, exosomes can transfer KCNQ1OT1 via autocrine to mediate the miR-30a-5p/USP22 pathway, then regulate the ubiquitination of PD-L1 and inhibit CD8 + T-cell responses ( Xian et al, 2021 ). Taken together, these results suggested that dysregulated exosomal lncRNAs may be meaningful biomarkers for cancer cell proliferation.…”