Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous tumor with an increased incidence worldwide accompanied by high mortality and dismal prognosis. Emerging evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes possess protective effects against various human diseases by transporting microRNAs (miRNAs or miRs). We aimed to explore the role of exosomal miR-15a derived from MSCs and its related mechanisms in HCC. Exosomes were isolated from transduced MSCs and co-incubated with Hep3B and Huh7 cells. miR-15a expression was examined by RT-qPCR in HCC cells, MSCs, and secreted exosomes. CCK-8, transwell, and flow cytometry were used to detect the effects of miR-15a or spalt-like transcription factor 4 (SALL4) on cell proliferative, migrating, invasive, and apoptotic properties. A dual-luciferase reporter gene assay was performed to validate the predicted targeting relationship of miR-15a with SALL4. Finally, in vivo experiments in nude mice were implemented to assess the impact of exosome-delivered miR-15a on HCC. The exosomes from MSCs restrained HCC cell proliferative, migrating, and invasive potentials, and accelerated their apoptosis. miR-15a was expressed at low levels in HCC cells and could bind to SALL4, thus curtailing the proliferative, migrating, and invasive abilities of HCC cells. Exosomes successfully delivered miR-15a to HCC cells. Exosomal miR-15a depressed tumorigenicity and metastasis of HCC tumors in vivo. Overall, exosomal miR-15a from MSCs can downregulate SALL4 expression and thereby retard HCC development.
Highlights
As a leading life-threatening malignancy, hepatocellular carcinoma (HCC) occupies ~85–90% of cases of primary liver cancers, which presents unsatisfying outcomes and limited therapeutic options [1, 2]
Successful characterization of Mesenchymal stromal cells (MSCs) and exosomes The morphology of isolated MSCs observed under a microscope revealed that MSCs grew in fibrous aggregates (Fig. 1A)
HCC accounts for ~90% of all newly diagnosed cases of primary liver cancer, which represents a burgeoning cause of cancerrelated mortality worldwide [20]
Summary
As a leading life-threatening malignancy, hepatocellular carcinoma (HCC) occupies ~85–90% of cases of primary liver cancers, which presents unsatisfying outcomes and limited therapeutic options [1, 2]. For patients with early-stage HCC, current managements, including tumor resection or ablation and liver transplantation, can achieve a clinical cure, while patients in advanced stages can only receive palliative treatments such as chemotherapy and pain relief [4]. As membranous vesicles, are responsible for transferring proteins, microRNAs (miRNAs or miRs), and long non-coding RNAs (lncRNAs) among cells, and represent promising new therapeutic targets for tumors [5, 6]. Mesenchymal stromal cells (MSCs) are frequently used as a source of cellular therapy because of their outstanding capacities for immunosuppression and regeneration [7].
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