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

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.

Molecular mechanisms of circular RNAs, transforming growth factor‐β, and long noncoding RNAs in hepatocellular carcinoma

“…Previously, MEG3 was incorporated into HCC cells by using a new delivery system, which suppressed tumor growth through p53. This finding showed that MEG3 may have tumor suppressive function in HCC . Also, MEG3 was identified to be a molecular sponge for miR‐664 inhibiting cell proliferation via miR‐664‐dependent ADH4 regulation .…”

“…The expression of lncRNAs can be manipulated by specific siRNAs or antisense oligonucleotides or exogenous overexpression . Previously, a study demonstrated that introduction of tumor suppressor MEG3 into HCC tumor via a novel delivery system promoted apoptosis, an effect that confirms the pharmacological value of lncRNA‐based therapy as an option with few adverse effects. Hence, we anticipate that further advanced studies exploiting modern research tools will expose deeper mechanisms of lncRNA action and add to the development of lncRNA‐based diagnostic and therapeutic agents for HCC management.…”

“…Maternally expressed 3 (MEG3) encodes lncRNA with a maternal inheritance pattern lncRNA . This lncRNA regulate HCC cells apoptosis and proliferation . Its transcription is low in human HCC tumors and was correlated with low OS levels, making it a potential predictor of HCC prognosis .…”

“…Its transcription is low in human HCC tumors and was correlated with low OS levels, making it a potential predictor of HCC prognosis . Among the mechanisms by which MEG3 inhibits tumor growth and development include its ability to activate p53 through a process involving promoting the stability and expression of genes . Previously, MEG3 was incorporated into HCC cells by using a new delivery system, which suppressed tumor growth through p53.…”

“…This finding showed that MEG3 may have tumor suppressive function in HCC. 163 Also, MEG3 was identified to be a molecular sponge for [129,131,159] miR-664 inhibiting cell proliferation via miR-664-dependent ADH4 regulation. 166 In summary, these findings implicate MEG3 as an anti-tumor agent, which can be exploited in the diagnosis as well as in the treatment of HCC.…”