Interferon-β gene-modified human bone marrow mesenchymal stem cells attenuate hepatocellular carcinoma through inhibiting AKT/FOXO3a pathway

Abstract

Objective:This study aims to investigate the using of bone marrow mesenchymal stem cells (BMSCs) genetically engineered to produce interferon-β (IFN-β) as a gene delivery system to treat hepatocellular carcinoma (HCC) in vitro and in vivo.Methods:To measure the effects on tumour cell growth in vitro, IFN-β-producing BMSCs (BMSC/IFN-β) were co-cultured with the HCC cell line HepG2 and Huh7. Enzyme-linked immunosorbent assay (ELISA) was used to detect the IFN-β secretion in the BMSC culture condition medium (CM). The effect of BMSC/IFN-β on HCC cells proliferation was examined both in vitro and in vivo by using MTT, colony formation assay, BrdU staining, cell cycle analysis, and xenografted NOD/SCID mouse tumour model. To examine the impact of BMSC/IFN-β on the AKT/FOXO3a signalling, RT–PCR and western blotting were performed.Results:The BMSC/IFN-β cells can stably secrete high levels of IFN-β. Both MTT and colony forming assay showed that HCC cells had a lower growth rate when cultured in BMSC/IFN-β-CM as compared with that in BMSC/vector-CM or DMEM culture group. Co-culture with BMSC/IFN-β-CM dramatically decreased the percentages of cells with incorporated BrdUrd. In BMSC/IFN-β-CM-treated HCC cells, the proportion of G1-phase cells increased but it decreased in the S phase of the cell. The BMSC/IFN-β inhibited HCC growth in NOD/SCID mice and proved the survival period of these mice. Compared with the control group, p21 and p27 expression of hepatoma cells increased, whereas cyclin D1 and phosphorylation of Rb expression decreased when co-cultured with BMSC/IFN-β-CM. It was associated with suppression of Akt activity and enhanced transcriptional activity of FOXO3a.Conclusion:The IFN-β gene-modified BMSCs can effectively inhibit the proliferation of HCC cells in vitro and in vivo through inhibiting AKT/FOXO3a pathway. These results indicate that BMSC/IFN-β are a powerful anticancer cytotherapeutic tool for HCC.

Intravenous administration of bone marrow-derived multipotent mesenchymal stromal cells enhances the recruitment of CD11b+ myeloid cells to the lungs and facilitates B16-F10 melanoma colonization

“…Of note, MSCs also have a tropism to inflammation sites and tumors [5]. This particular characteristic has driven the use of genetically engineered MSCs to deliver anti-cancer molecules directly to developing tumors [6].…”

“…hepatocytes) from apoptosis [4]. Furthermore, it has been postulated that BM-MSCs possess tropism to injury sites and tumors [5], which have justified their use as cellular vehicles for directly delivering anti-cancer drugs into tumors [6].…”

Inhibitory effects of interferon‐β on hepatocellular carcinoma HepG2 via Akt/STAT phosphorylation

“…Activation of the Akt pathway has been contributed to increase tumor aggressiveness [18]. Xie et al [23] reported the association of suppression of Akt activity and enhanced transcriptional activity of FOXO3a in the cells treated with IFN-b. In consistence with previously identified significance of the Akt oncogenic kinase in HCC, our data indicate that Akt phosphorylation inhibited by IFNb is associated with reducing Akt activation.…”

“…It is noteworthy that FOXO3a and Akt-regulated transcription factor have been found to be functionally important in the development of human HCC [20][21][22]. Xie et al [23] reported the association of suppression of Akt activity and enhanced transcriptional activity of FOXO3a in the cells treated with IFN-b. Thus, our data provide a line of evidence for the regulatory effect of IFN-b on Akt phosphorylation in HepG2 cells.…”

JAM-A promotes wound healing by enhancing both homing and secretory activities of mesenchymal stem cells

“…Xie et al [4] combined tumour necrosis factor α (TNF-α) and TNF-β and interferon (IFN-β) β and IFN-γ , and found that the in vitro migratory ability of MSCs was increased, but that the effect of migrating to the affected site was 'not sufficient to enhance wound repair'. In another study, Cheng et al [5] reported that MSCs with high expression of chemokine receptor 4 (CXCR4) administered via the tail vein after transfection homed to the ischaemic myocardium better than control cells did.…”