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

// Le Chang 1, 2 , Guojing Wang 1, 2 , Tingting Jia 3 , Lei Zhang 1, 4 , Yulong Li 1, 2 , Yanxi Han 1 , Kuo Zhang 1, 2 , Guigao Lin 1 , Rui Zhang 1 , Jinming Li 1, 2 , Lunan Wang 1, 2 1 National Center for Clinical Laboratories, Beijing Hospital, Beijing, People's Republic of China 2 Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China 3 Department of Clinical Laboratory, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China 4 Peking University Fifth School of Clinical Medicine, Beijing, People's Republic of China Correspondence to: Jinming Li, e-mail: [email protected] Lunan Wang, e-mail: [email protected] Keywords: hepatocellular carcinoma, maternally expressed gene 3, MS2 virus-like particles, epidermal growth factor receptor, GE11 Received: January 21, 2016      Accepted: March 02, 2016      Published: March 16, 2016 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.

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