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

Xin Liang Lv ,Chao Yong Tu ,Kun Zhang,Chuan Jiang,Min-Jie Shang,Chao-Yong Tu,Xin-Liang Lv,Chu-Xiao Shao,Jin-De Zhu

doi:10.1042/bsr20194026

Xin Liang Lv , Chao Yong Tu + Show 7 more

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https://doi.org/10.1042/bsr20194026

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Abstract

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.

Highlights

Hepatocellular carcinoma (HCC), which is one of the most common malignancies all over the world, is a major cause of death associated with cancer [1]
In order to examine the possible target genes of miR-199a-3p, several target genes of micro RNA (miRNA) were obtained by retrieving in the bioinformatics software Targetscan, PicTar, PITA, microT and miRmap, and related graphs were plotted (Figure 1B)
Literature has revealed that ZEB1 [40], MTOR [41] and DNMT3A [42] are closely related to drug resistance of tumors

Summary

Introduction

Hepatocellular carcinoma (HCC), which is one of the most common malignancies all over the world, is a major cause of death associated with cancer [1]. A large variety of therapies have been used for treating liver cancer, the prognosis of HCC is still poor, and its 5-year survival rate is below 20% due to its high metastasis and recurrence rates [5,6]. The drug resistance to DDP, a first-line chemotherapeutic drug for clinical treatment of HCC, seriously affects its efficacy and is one of the main reasons for the low 5-year survival rate of clinical patients. There is still no effective prediction and treatment for the development of HCC chemoresistance [8]. It is of great theoretical significance and application value to study the mechanism of HCC chemoresistance [9]. Studies have found the diverse mechanism of DDP resistance, including drug-related molecular and genetic changes [10], drug uptake accumulation and transport disorders [11]

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