MicroRNA-214 enriched exosomes from human cerebral endothelial cells (hCEC) sensitize hepatocellular carcinoma to anti-cancer drugs

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver tumor worldwide. Current medical therapy for HCC has limited efficacy. The present study tests the hypothesis that human cerebral endothelial cell-derived exosomes carrying elevated miR-214 (hCEC-Exo-214) can amplify the efficacy of anti-cancer drugs on HCC cells. Treatment of HepG2 and Hep3B cells with hCEC-Exo-214 in combination with anti-cancer agents, oxaliplatin or sorafenib, significantly reduced cancer cell viability and invasion compared with monotherapy with either drug. Additionally, the therapeutic effect of the combination therapy was detected in primary tumor cells derived from patients with HCC. The ability of hCEC-Exo-214 in sensitizing HCC cells to anti-cancer drugs was specific, in that combination therapy did not affect the viability and invasion of human liver epithelial cells and non-cancer primary cells. Furthermore, compared to monotherapy with oxaliplatin and sorafenib, hCEC-Exo-214 in combination with either drug substantially reduced protein levels of P-glycoprotein (P-gp) and splicing factor 3B subunit 3 (SF3B3) in HCC cells. P-gp and SF3B3 are among miR-214 target genes and are known to mediate drug resistance and cancer cell proliferation, respectively. In conclusion, the present in vitro study provides evidence that hCEC-Exo-214 significantly enhances the anti-tumor efficacy of oxaliplatin and sorafenib on HCC cells.

Exosomes as potential diagnosis and treatment for liver cancer

“…Table 4 [ 67 - 69 ] focuses on the carrier roles of exosomes in HCC. Drug-carrying exosomes were injected into tumor-prone mice to observe the effects of the drugs.…”

Exosomes as Natural Nanocarriers for RNA-Based Therapy and Prophylaxis

“…Transfection of plasmids, or viral transduction, can be performed to express target RNAs in donor cells, followed by incorporation of these RNAs into exosomes. This approach can be implemented for both miRNA [ 151 , 152 , 153 ] and long mRNA [ 154 , 155 , 156 , 157 ].…”

Microvesicles: the functional mediators in sorafenib resistance

“…Similarly, long non-coding RNA (lnc-ROR and lnc-VLDLR)-enriched HCC cells-secreted vesicles (especially after sorafenib exposure) were proved to reduce apoptosis induced by chemotherapy [88,89] . However, MVs released from modified adipose tissue-derived MSCs have been shown to carry miR-199a/miR-122 and have the ability to improve chemosensitivity in HCC [90,91] . Elevated miR-214 in human cerebral endothelial cellreleased vesicles was noted to enhance the anti-tumor efficacy of sorafenib [92] [Figure 3].…”

“…By combined regulation of Akt/mTOR/PTEN, EVs secreted from human liver stem cells were proved to upgrade CSCs' sensitivity to sorafenib [101] . Lou et al [91] stated that treating HCCs with exosomes derived from miR-122 overexpressed AMSCs rendered HCCs more responsive to sorafenib. In the same way, miR-744-enriched exosomes have been demonstrated to be a potential tool for reducing sorafenib resistance [102] .…”