Therapeutic strategy with artificially-designed i-lncRNA targeting multiple oncogenic microRNAs exhibits effective antitumor activity in diffuse large B-cell lymphoma

// Yinghan Su 1, 2, * , Bin Sun 2, * , Xuejing Lin 2, * , Xinying Zhao 3 , Weidan Ji 2 , Miaoxia He 3 , Haihua Qian 2 , Xianmin Song 3 , Jianmin Yang 3 , Jianmin Wang 3 , Jie Chen 3 1 School of Life Science, University of Liverpool, Liverpool, L3 4PH, UK 2 Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China 3 Department of Hematology & Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200168, China * These authors have contributed equally to this work Correspondence to: Jie Chen, email: chenjiedoctor@163.com Keywords: diffuse large B-cell lymphoma, artificial long non-coding RNA, oncogenic microRNA, xenograft model, therapeutic strategy Received: December 10, 2015 Accepted: April 18, 2016 Published: May 09, 2016 ABSTRACT In diffuse large B-cell lymphoma (DLBCL), many oncogenic microRNAs (OncomiRs) are highly expressed to promote disease development and progression by inhibiting the expression and function of certain tumor suppressor genes, and these OncomiRs comprise a promising new class of molecular targets for the treatment of DLBCL. However, most current therapeutic studies have focused on a single miRNA, with limited treatment outcomes. In this study, we generated tandem sequences of 10 copies of the complementary binding sequences to 13 OncomiRs and synthesized an interfering long non-coding RNA (i-lncRNA). The highly-expressed i-lncRNA in DLBCL cells would compete with the corresponding mRNAs of OncomiR target genes for binding OncomiRs, thereby effectively consuming a large amount of OncomiRs and protecting many tumor suppressor genes. The in vitro experiments confirmed that the i-lncRNA expression significantly inhibited cell proliferation, induced cell cycle arrest and apoptosis in DLBCL cell lines, mainly through upregulating the expression of PTEN, p27 kip1 , TIMP3, RECK and downregulating the expression of p38/MAPK, survivin, CDK4, c-myc. In the established SUDHL-4 xenografts in nude mice, the treatment strategy involving adenovirus-mediated i-lncRNA expression significantly inhibited the growth of DLBCL xenografts. Therefore, this treatment would specifically target the carcinogenic effects of many OncomiRs that are usually expressed in DLBCL and not in normal cells, such a strategy could improve anti-tumor efficacy and safety and may be a good prospect for clinical applications.