RETRACTED: Overexpressed Tumor Suppressor Exosomal miR-15a-5p in Cancer Cells Inhibits PD1 Expression in CD8+T Cells and Suppresses the Hepatocellular Carcinoma Progression

Abstract

BackgroundHepatocellular carcinoma (HCC) is the most common primary liver tumor, and the main reason is the unclear pathogenesis of HCC, which leads to a high fatality rate of HCC. Therefore, it is of great clinical significance to explore the molecular mechanism of HCC and find a targeted therapeutic approach from the molecular level.Materials and MethodsMicroRNA-15a-5p (miR-15a-5p) expression level was measured by bioinformatics and qRT-PCR. Luciferase assay and RIP assays were used to verify the relationship between programmed cell death protein 1 (PD1) PD 1 with miR-15a-5p. Exosomes were identified using TEM, Zetasizer Nano ZS, and western blot. Edu, Transwell, and scratch assay were performed to explore the role of miR-15a-5p or exo-miR-15a-5p on HepG2 cells progression.ResultsMicroRNA-15a-5p (miR-15a-5p) was decreased in HCC tissues and cell lines, which indicated a poor prognosis. Overexpression of miR-15a-5p inhibited viability, proliferation, migration and invasion of HepG2 cells. Then, we isolated exosomes from cancer cells, and found that miR-15a-5p was packaged into exosomes from cancer cells. Furthermore, exo-miR-15a-5p was secreted into CD8+ T cells, then directly inhibited PD1 expression via targeted binding. Then, we co-cultured CD8+ T cells transfected with PD1 with HepG2 transfected with miR-15a-5p, PD1 remitted the inhibitory role of miR-15a-5p on HCC progression.ConclusionTogether, present study revealed exo-miR-15a-5p from cancer cells inhibited PD1 expression in CD8+ T cells, which suppressed the development of HCC.

Exploration of Extracellular Vesicle miRNAs, Targeted mRNAs and Pathways in Prostate Cancer: Relation to Disease Status and Progression

“…Disposing of tumour suppressors could bring a growth advantage to PCa cells [71]. In support of this, Zhang et al observed this kind of a difference in the tumour suppressor miR-15a-5p levels of hepatocellular carcinoma EV and cells [72]. Additionally, in the case of mRNAs, the transcripts in parental cells and their EV may differ [73].…”

Blockade of PD‐1 and CTLA‐4: A potent immunotherapeutic approach for hepatocellular carcinoma

“…34 Moreover, it also inhibited the function of NK cells by increasing TIM-3 expression levels through the degradation of miR-449c-5p, thus resulting in resistance to anti-PD-1 therapy. 34,35 Therefore, reducing the expression levels of circUHRF1 through the exosomal circUHRF1/miR-449c-5p/TIM-3 pathway improves the efficacy of anti-PD-1 therapy, which might provide a promising method for HCC immunotherapy. T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) are expressed on NK cells, regulatory CD4 + T cells, and effector T cells.…”

“…CircUHRF1 inhibited the secretion of natural killer (NK) cell‐derived TNF‐α and IFN‐γ 34 . Moreover, it also inhibited the function of NK cells by increasing TIM‐3 expression levels through the degradation of miR‐449c‐5p, thus resulting in resistance to anti‐PD‐1 therapy 34,35 . Therefore, reducing the expression levels of circUHRF1 through the exosomal circUHRF1/miR‐449c‐5p/TIM‐3 pathway improves the efficacy of anti‐PD‐1 therapy, which might provide a promising method for HCC immunotherapy.…”

Role of Exosomes in Immunotherapy of Hepatocellular Carcinoma

“…Tumor-cell-derived exosomes can be directly transported into CD8+ T cells, tumor-infiltrating T cells, or regulatory T cells to inhibit their anti-tumor function or modulate their cellular behaviors [ 30 , 31 , 32 , 33 ]. Furthermore, HCC-derived exosomes can induce nature killer (NK) cell activation, attenuate NK cell cytotoxicity, and arrest them to secret cytokines [ 34 , 35 , 36 ].…”