Abstract
BackgroundMiR-199a-3p (miR-199a) can enhance the chemosensitivity of hepatocellular carcinoma (HCC). Because of the easy degradation of miRNA by direct infusion, effective vehicle-mediated delivery of miR-199a may represent a new strategy for improving HCC chemotherapy. Considering mesenchymal stem cell (MSC)-derived exosomes as promising natural nanovectors for drug and molecule delivery, we aimed to determine whether exosomes from adipose tissue-derived MSCs (AMSCs) could be used to deliver miR-199a and improve HCC chemosensitivity.MethodsMiR-199a-modified AMSCs (AMSC-199a) were constructed by miR-199a lentivirus infection and puromycin selection. MiR-199-modified exosomes (AMSC-Exo-199a) were isolated from the supernatant of AMSC-199a and were assessed by transmission electron microscopy, nanoparticle tracking analysis, and flow cytometry analysis. The expression levels of miR-199a in HCC samples, AMSCs, exosomes, and HCC cells were quantified by real-time PCR. The effects of AMSC-Exo-199a on HCC chemosensitivity were determined by cell proliferation and apoptosis assays and by i.v. injection into orthotopic HCC mouse models with doxorubicin treatment. MTOR, p-4EBP1 and p-70S6K levels in HCC cells and tissues were quantified by Western blot.ResultsAMSC-Exo-199a had the classic characteristics of exosomes and could effectively mediate miR-199a delivery to HCC cells. Additionally, AMSC-Exo-199a significantly sensitized HCC cells to doxorubicin by targeting mTOR and subsequently inhibiting the mTOR pathway. Moreover, i.v.-injected AMSC-Exo-199a could distribute to tumor tissue and markedly increased the effect of Dox against HCC in vivo.ConclusionsAMSC-Exo-199a can be an effective vehicle for miR-199a delivery, and they effectively sensitized HCC to chemotherapeutic agents by targeting mTOR pathway. AMSC-Exo-199a administration may provide a new strategy for improving HCC chemosensitivity.
Highlights
MiR-199a-3p can enhance the chemosensitivity of hepatocellular carcinoma (HCC)
MiR-199a-3p level is related to chemosensitivity of HCC cells By examining the miR-199a-3p expression in 10 randomly selected HCC tissues and paired adjacent noncancerous liver tissues, we found that 8 out of 10 HCCs (80%) had decreased miR-199a-3p expression compared with that of the corresponding noncancerous hepatic tissues (Fig. 1a)
Adipose tissue-derived mesenchymal stem cell (MSC) (AMSC)-Exo mediates miR-199a-3p transfer into HCC cells To determine whether AMSC-derived exosomes could be used as effective vehicles for miR-199a-3p delivery to improve HCC chemotherapy, AMSCs were modified with miR-199a-3p (AMSC-199a) by LV-199a infection, and elevated miR-199a-3p level in AMSC-199a was confirmed by qRT-polymerase chain reaction (PCR) (Fig. 2a)
Summary
MiR-199a-3p (miR-199a) can enhance the chemosensitivity of hepatocellular carcinoma (HCC). Because of the easy degradation of miRNA by direct infusion, effective vehicle-mediated delivery of miR-199a may represent a new strategy for improving HCC chemotherapy. Considering mesenchymal stem cell (MSC)-derived exosomes as promising natural nanovectors for drug and molecule delivery, we aimed to determine whether exosomes from adipose tissue-derived MSCs (AMSCs) could be used to deliver miR-199a and improve HCC chemosensitivity. The progression of HCC and the acquisition of multidrug resistance are critically influenced by miRNAs through the regulation of key genes in cellular regulatory pathways [4]. Restoration of miR-199a-3p in HCC cell lines leads to reduced cell proliferation, invasion and migration, as well as enhanced doxorubicin sensitivity by suppressing the expressions of its target genes including YAP1 [9], CD151 [10] and mTOR [11]. Delivery of miR-199a-3p to HCC cells might be a potential strategy for increasing HCC chemosensitivity
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