Exosomes Derived from microRNA-27a-3p Overexpressing Mesenchymal Stem Cells Inhibit the Progression of Liver Cancer through Suppression of Golgi Membrane Protein 1

Abstract

Hepatocellular carcinoma (HCC) remains a significant health burden to date. Its early diagnosis and treatment are complicated by the lack of early diagnosis markers and multidrug resistance. microRNA regulation of HCC oncogenes are among the new diagnostic and therapeutic strategies being explored, although the mode of delivery of a therapeutic dose of the miRNA remains a challenge. In this study, we explored the use of exosomes from umbilical mesenchymal stem cells transfected with miR-27a-3p to interact with the oncogene GOLM1 in HCC and inhibit HCC progression both in vitro and in vivo. We first determined and compared the expression levels of miR-27a-3p in blood, various cell lines and tissues of HCC and their corresponding normal controls. We then employed bioinformatics analysis to determine the gene target for miR-27a-3p in HCC and later transfected upregulated miR-27a-3p in mesenchymal stem cells, and treated HCC cells with exosomes extracted from the transfected stem cells. We then created mouse models of HCC using balbc/nude mice and equally treated them with exosomes from miR-27a-3p transfected stem cells. The results showed that miR-27a-3p is downregulated in blood, cell lines, and tissues of HCC patients compared to normal controls. Exosomes from the miR-27a-3p transfected mesenchymal stem cells prevented HCC cell proliferation, invasion, and metastasis both in vitro and in vivo. Upregulation of miR-27a-3p prevented HCC through interacting with and downregulating GOLM1 as its target oncogene. In conclusion, miR-27a-3p is a potential therapeutic target for HCC acting through GOLM1.

RNA-RNA interactions between Respiratory syncytial virus and miR-26 and miR-27 are associated with regulation of cell cycle and antiviral immunity

“…Analysis of the top up-regulated targets by the miR-27 inhibitor further highlights cell cycle, metabolism, and antiviral immunity targets as susceptible to miR-27 inhibition. The top four targets that are significantly upregulated are: CCNG1 (Cyclin G1) and PHLPP2 which have both been shown to induce cell cycle arrest (57–61), GOLM1 (Golgi membrane protein 1, also known as GP73) which is a validated miR-27 target that is emerging as a key regulator of IL-6 also linked to innate immunity and RSV infection (62–66) and LIMK1 (LIM domain kinase 1, Fig 4E), a serine/threonine-protein kinase involved in remodelling of the cytoskeleton. LIMK1 has been shown to be an important host factor for many viral life cycles, including HIV, HSV-1, and Influenza virus (67–71) and LIMK1 inhibitors are currently explored as broad-spectrum antiviral drugs (72).…”

Unveiling the impact of GOLM1/GP73 on cytokine production in cancer and infectious disease

“…The higher expression of GOLM1 is associated with decreased survival in lung cancer, melanoma, colorectal cancer, uveal melanoma and HCC 29,40,43,44 . As recently reviewed elsewhere, 9 GOLM1 expression can be increased by multiple extracellular factors in the tumor microenvironment, including hypoxia, 22 various miRNAs, 45–47 and the cytokines IL‐1β, 48 IL‐6 and Oncostatin M 49 . However, the upregulation of GOLM1 is not a universal phenomenon in cancer, because lower levels of GOLM1 have been reported in colon cancer 23 …”

Exosomes: Diagnostic and Therapeutic Implications in Cancer

“…miR-27a-3p is decreased in the cells and tissues of patients with hepatic cancers. Exosomes derived from miR-27a-overexpressing MSCs suppress the progression of hepatic cancer by decreasing Golgi membrane protein 1 (GOLM1) expression [ 80 ]. Exosomal miR-10527-5p is decreased in both the plasma exosomes and tumor tissues of esophageal squamous cell carcinoma (ESCC) patients.…”