Bone Marrow Mesenchymal Stem Cells-Derived Exosomes Upregulate MicroRNA-424-5p to Suppress Hepatocellular Carcinoma Cell Growth by Inhibiting Forkhead Box K1

Abstract Bone marrow mesenchymal stem cells (BM-MSCs) have been shown to exert a potential therapeutic effect during tumor treatment and it has been proved that exosomes derived from BM-MSCs play crucial roles in the progression of malignant tumors. The current study aims to investigate the effect of BM-MSC-derived exosomal microRNA-424-5p (miR-424-5p) on hepatocellular carcinoma (HCC) progression. The expression of miR-424-5p was compared between HCC and adjacent normal tissues, and its prognosis value was analyzed. Additionally, exosomes were extracted from the BM-MSCs and their identity was verified. Luciferase reporter assay was conducted to identify the putative binding sites between miR-424-5p and the 3’-UTR of forkhead box K1 (FOXK1). The BM-MSC-derived exosomes were co-cultured with HCC cells to assess the effect of the BM-MSC-derived exosomes, miR-424-5p, and FOXK1 on the proliferation, migration, invasion, and in vivo tumorigenesis of the HCC cells. Then, the expression of FOXK1 was also examined in HCC and normal tissues. miR-424-5p was downregulated and FOXK1 was upregulated in HCC tissues and cells. BM-MSC-derived exosomes upregulated miR-424-5p expression to suppress the proliferation, migration, invasion, and in vivo tumorigenesis of HCC cells. Knockdown of FOXK1 also repressed the malignant behavior of the HCC cells, and FOXK1 was verified as the target of miR-424-5p. The role of FOXK1 silencing in HCC cells was reversed by miR-424-5p downregulation. Our results suggested that BM-MSC-derived exosomes upregulated miR-424-5p expression to restrain HCC cell growth and invasion via inhibition of FOXK1 expression and as a result, decelerating HCC development.