Armored long non-coding RNA MEG3 targeting EGFR based on recombinant MS2 bacteriophage virus-like particles against hepatocellular carcinoma

Le Chang,Kuo Zhang,Jinming Li,Lunan Wang,Lei Zhang,Yulong Li,Tingting Jia,Yanxi Han,Guigao Lin,Rui Zhang,Guojing Wang

doi:10.18632/oncotarget.8115

Abstract

Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed cancers worldwide. However, the treatment of patients with HCC is particularly challenging. Long non-coding RNA maternally expressed gene 3 (MEG3) has been identified as a potential suppressor of several types of tumors, but the delivery of long RNA remains problematic, limiting its applications. In the present study, we designed a novel delivery system based on MS2 virus-like particles (VLPs) crosslinked with GE11 polypeptide. This vector was found to be fast, effective and safe for the targeted delivery of lncRNA MEG3 RNA to the epidermal growth factor receptor (EGFR)-positive HCC cell lines without the activation of EGFR downstream pathways, and significantly attenuated both in vitro and in vivo tumor cell growth. Our study also revealed that the targeted delivery was mainly dependent on clathrin-mediated endocytosis and MEG3 RNA suppresses tumor growth mainly via increasing the expression of p53 and its downstream gene GDF15, but decreasing the expression of MDM2. Thus, this vector is promising as a novel delivery system and may facilitate a new approach to lncRNA based cancer therapy.

Highlights

Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed cancers worldwide, and is the second leading cause of cancer death globally [1]
Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) results revealed that the molecular weight of the MS2 coat protein was approximately 10–14 kDa (Figure 2C), and transmission electron microscope (TEM) results indicated that the virus-like particles (VLPs) had a diameter of approximately 26–30 nm (Figure 2E)
The results indicated that the VLPs-maternally expressed gene 3 (MEG3) contained an approximate 1600-bp MEG3 RNA sequence and that the VLPs-NC did not contain the specific RNA fragment (Figure 2D)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed cancers worldwide, and is the second leading cause of cancer death globally [1]. The only vector currently available for use with MEG3 is a plasmid vector containing a MEG3 cDNA fragment, and liposome-mediated transfection is the only method of delivery [12, 15,16,17,18,19]. Deficiencies such as limited transduction efficiency, cytotoxicity, and integration-induced tumorigenesis, remain a concern that www.impactjournals.com/oncotarget significantly limits the effect and applications of MEG3 therapy

Methods

Results

Conclusion