Tumor stem cell-derived exosomal microRNA-17-5p inhibits anti-tumor immunity in colorectal cancer via targeting SPOP and overexpressing PD-L1

Abstract

Exosomes are known to transmit microRNAs (miRNAs) to affect human cancer progression, and miR-17-5p has been manifested to exert facilitated effects on colorectal cancer (CRC) progression, while the role of tumor stem cells-derived exosomal miR-17-5p in CRC remains unknown. We aim to explore the effect of CRC stem cells-derived exosomes (CRCSC-exos) conveying miR-17-5p on CRC. The exosomes were isolated from CRC stem cells and identified. HCT116 cells were transfected with speckle-type POZ protein (SPOP) interfering vector or co-cultured with exosomes carrying miR-17-5p mimic/inhibitor. Then, the proliferation, migration, invasion, and apoptosis of the cells were determined. The xenograft mouse model was constructed using BALB/C mice and the serum levels of T cell cytokines were assessed. Expression of miR-17-5p, SPOP, CD4, CD8 and programmed death ligand 1 (PD-L1) was detected. The targeting relationship between miR-17-5p and SPOP was verified. MiR-17-5p was upregulated and SPOP was downregulated in CRC tissues. CRCSC-exos transmitted miR-17-5p to HCT116 cells to promote malignant behaviors and suppress anti-tumor immunity of HCT116 cells. The overexpressed SPOP exerted opposite effects. SPOP was confirmed as a target gene of miR-17-5p. Upregulated CRCSC-exosomal miR-17-5p inhibits SPOP to promote tumor cell growth and dampen anti-tumor immunity in CRC through promoting PD-L1.

Association between colorectal cancer and expression levels of miR-21, miR-17-5P, miR-155 genes and the presence of Fusobacterium nucleatum in biopsy samples obtained from Iranian patients

“…In addition to colorectal cancer, the change in miR-21 gene expression is particularly important in other cancers, such as lung, breast, and stomach cancer [ 36 – 38 ]. The same as our study, other studies, including Huang et al in China [ 39 ], Ibrahiem et al in Saudi Arabia (2020) [ 40 ], and Sun et al in China [ 41 ] the expression level of miR-17-5P gene in CRC patients showed a significant increase. It has been shown that CRC patients’ intestinal microbiota is dominated by opportunistic proinflammatory pathogens such as Fusobacterium.…”

The E3 ubiquitin ligases regulate PD-1/PD-L1 protein levels in tumor microenvironment to improve immunotherapy

“…Specifically, c-Myb increased miR-145-5p expression and in turn reduced SPOP and regulated PD-L1, leading to suppression of T cell functions and induction of immune escape in esophageal adenocarcinoma cells ( 64 ). Cancer stem cell-derived exosomal miR-17-5p reduced SPOP expression and increased PD-L1 accumulation, leading to suppression of antitumor immunity in colorectal cancer cells ( 65 ). Recently, SPOP was found to increase the movement of PD-1 away from PD-L1 in spatial localization, and enhanced tumor metastasis in cervical cancer ( 66 ).…”

Integrated whole transcriptome profiling of circRNAs reveals a convoluted crosstalk in competing endogenous RNAs regulatory network in Colorectal Cancer

“…Likewise, MYC proto-oncogene that is commonly dysregulated in human malignancies can induce expression of the hsa-mir-17-92 cluster at the transcriptional level 49 . Hsa-miR-17-5p is involved in EMT, metastasis, tumor cell proliferation, cell cycle progression, cell migration, invasion, and angiogenesis in CRC [50][51][52][53][54][55][56] . Two studies have found that hsa-miR-19b-3p is involved in response to chemotherapy and radiotherapy in CRC 57,58 .…”