Exosomes function as nanoparticles to transfer miR-199a-3p to reverse chemoresistance to cisplatin in hepatocellular carcinoma

Abstract

<jats:title>Abstract</jats:title> <jats:p>Hepatocellular carcinoma (HCC) is a frequently seen malignant tumor globally. The occurrence of cisplatin (DDP) resistance is one of the main reasons for the high mortality of HCC patients. Therefore, it is of great theoretical significance and application value to explore the mechanism of chemotherapy resistance. Drug resistance can be modulated by exosomes containing mRNAs, micro RNAs (miRNAs) and other non-coding RNA (ncRNAs). Exosomal miR-199a-3p (Exo-miR-199a-3p) was subjected to extraction and verification. Whether exo-miR-199a-3p could make HCC cells sensitive to DDP in vitro was verified via flow cytometry, Cell Counting Kit-8 (CCK-8) assay, immunofluorescence assay and Transwell assay. Intravenous injection of exo-miR-199a-3p and intraperitoneal injection of DDP were carried out in vivo. Moreover, the possible targets of miR-199a-3p were screened through bioinformatics analysis, which were ascertained by Western blotting (WB). Then, miR-199a-3p levels in human normal liver epithelial cell line HL-7702 and HCC cell lines HuH7 and HuH7/DDP were elevated in a concentration-dependent manner. Exo-miR-199a-3p has abilities to adjust underlying targets and conjugate cells, to repress cells to invade, stimulate their apoptosis and abate their ability. Additionally, the caudal injection of exo-miR-199a-3p reversed the chemoresistance of tumors and slowed down their growth in the body owing to the up-regulation of miR-199a-3p and down-regulation of underlying target proteins in tumors. Finally, exo-miR-199a-3p was found to overturn the HCC’s resistance to DDP, and it may function in DDP-refractory HCC therapy as an underlying option in the future.</jats:p>

Role of Exosomes in Immune Microenvironment of Hepatocellular Carcinoma

“…Analogously, exosomal miR-744 inhibits the proliferation of HCC cells by targeting PAX2 and increases the sensitivity to sorafenib [73]. Furthermore, exosomes derived from human embryonic kidney epithelial cells function as nanoparticles to transfer miR-199a-3p, thereby reversing the chemoresistance of HCC cells to cisplatin [74].…”

Exosome in Hepatocellular Carcinoma: an update

“…However, the emergence of drug resistance in HCC cells often hinders the therapeutic effects of chemical drugs. Studies on HCC cells have shown that exosomal miR-199a-3p reversed tumor chemoresistance and reduced the resistance of HCC to cisplatin 68 . The exosomes of mesenchymal stem cells derived from adipose tissue effectively mediated the delivery of miR-199a to HCC cells, while AMSC-Exo-199a targeted mTOR and subsequently inhibited the mTOR pathway, making HCC cells sensitive to adriamycin.…”

Expedition into Exosome Biology: A Perspective of Progress from Discovery to Therapeutic Development

“…In addition, to the efforts being made to increase stability during long-term storage, research is also being conducted to identify means of delivering drugs to tumors located in fragile tissues [ 220 , 221 ]. Administration of exosome-based therapeutics via intravenous injection has been commonly used to deliver drugs to brain, pancreas, and tumors in other tissues [ 165 , 167 , 168 , 172 , 198 , 222 , 223 , 224 , 225 , 226 ], and the endogenic origins of exosomes help them escape removal by immune cells [ 227 ]. Exosome-based delivery of therapeutics increases drug stability and enables high drug loadings in body fluids [ 227 ], and lack of lymphatic drainage and the presence of fewer blood vessels aid in the retention of exosomes in tumorigenic tissues [ 12 , 228 , 229 ], which enhances their therapeutic efficacies.…”