title: Therapeutic strategy with artificially-designed i-lncRNA targeting multiple oncogenic microRNAs exhibits effective antitumor activity in diffuse large B-cell lymphoma.
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, p27kip1, 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.
authors.affiliation: School of Life Science, University of Liverpool, Liverpool, L3 4PH, UK.|Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Yinghan
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Hematology & Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200168, China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Weidan
authors.initials: W
authors.lastname: Ji
authors.affiliation: Department of Hematology & Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200168, China.
authors.forename: Miaoxia
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Haihua
authors.initials: H
authors.lastname: Qian
authors.affiliation: Department of Hematology & Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200168, China.
authors.forename: Xianmin
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Hematology & Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200168, China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Hematology & Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200168, China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hematology & Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200168, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000235:genetics; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D009368:Neoplasm Transplantation; D009857:Oncogenes; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D062085:RNA, Long Noncoding; D049452:Green Fluorescent Proteins
keywords: artificial long non-coding RNA; diffuse large B-cell lymphoma; oncogenic microRNA; therapeutic strategy; xenograft model