Exosome-Mediated MiR-155 Transfer Contributes to Hepatocellular Carcinoma Cell Proliferation by Targeting PTEN

Abstract

BackgroundMost eukaryocytes release nano vesicles (30–120 nm), named exosomes, to various biological fluids such as blood, lymph, and milk. Hepatocellular carcinoma (HCC) is one of the tumors with the highest incidence rate in primary malignant carcinoma of the liver. However, the mechanism of HCC proliferation remains elusive. In this study, we aim to explore whether HCC cell-derived exosomes affect the proliferation of cancer cells.Material/MethodsExosomes were isolated from HCC cells by ultracentrifugation and were visualized the phenotype by transmission electron microscopy. Cell proliferation was detected by Cell Counting Kit-8 assays and EdU (5-ethynyl-2-deoxyuridine) incorporation assays. Dual-luciferase assays were performed to validate the paired correlation of miR-155 and 3′-UTR of PTEN (gene of phosphate and tension homology deleted on chromosome 10). A xenograft mice model was constructed to verify the effect of exosome-mediated miR-155 on cell proliferation in vivo.ResultsOur finding showed that miR-155 was enriched in exosomes released from HCC cells. The exosome-containing miR-155 transferred into new HCC targeted cells and lead to the elevation of HCC cells’ proliferation. Besides, the exosomal miR-155 directly bound to 3′-UTR of PTEN leading to the reduction of relevant targets in recipient liver cells. The knockdown of PTEN attenuated the proliferation of HCC cells treated with the exosomal miR-155. Moreover, nude-mouse experiment results revealed a promotional effect of the exosomal miR-155 on HCC cell-acquired xenografts.ConclusionsOur study indicated that exosomal-specific miR-155 transfers to adjacent and/or more distant cells and stimulates the proliferation of HCC cells.

The Crosstalk between Tumor Cells and the Microenvironment in Hepatocellular Carcinoma: The Role of Exosomal microRNAs and Their Clinical Implications

“…[72] In the cell-to-cell communication network, the role of other miRNA targeting PTEN is evidenced by the transfer of Hep-3B-derived exosomes, enriched in miR-155, to HepG2 cells. The downregulation of PTEN resulted in a Phosphatidylinositol 3 Kinase (PI3K)-AKT pathway activation, determining cell proliferation [62]. Although this paracrine regulatory network, highlighting the role of mir-10b, -21, and -155 in HCC, proliferation and EMT, have never been proven in the same experimental model, it may suggest a possible synergism of cancer cell-derived exosomal miRNAs in fostering cancer progression by enhancing neighbor cancer cell growth (Table 1, Figure 1).…”

Exosomal MicroRNAs as Mediators of Cellular Interactions Between Cancer Cells and Macrophages

“…The inhibition of SOCS1 reverses the effects of mR-155 on cancer cell proliferation (105). Exosomal miR-155 of hepatocellular carcinoma cells (HCC) binds to the 3 ′ -untranslated region (UTR) of PTEN, and stimulates the proliferation of HCC (106).…”

Flaming the fight against cancer cells: the role of microRNA-93

“…PTEN plays a significant role in modulation of cell cycle and proliferation. It seems that PTEN exerts an antitumor impact since its expression undergoes down-regulation during cancer progression [112,113]. Investigation of molecular pathways demonstrates that miR-93-5p enhances the malignancy and proliferation of EC cells by down-regulation of PTEN/PI3K/Akt axis and its downstream targets p21 and cyclin D1 [114].…”