Systematic analysis of berberine-induced signaling pathway between miRNA clusters and mRNAs and identification of mir-99a∼125b cluster function by seed-targeting inhibitors in multiple myeloma cells

• Published in: RNA biology Vol. 12; no. 1; pp. 82 - 91
• Main Authors: Feng, Maoxiao, Luo, Xiaochuang, Gu, Chunming, Li, Yumin, Zhu, Xuejiao, Fei, Jia
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2015
• Subjects: Alkaloids - pharmacology; antineoplastic activity; apoptosis; berberine; Berberine - pharmacology; bioinformatics; cell cycle checkpoints; Cell Line, Tumor; G2 Phase Cell Cycle Checkpoints; gene expression regulation; genes; Humans; interphase; messenger RNA; microRNA; MicroRNAs - metabolism; mir-99a∼125b cluster; mitogen-activated protein kinase; multiple myeloma; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; myeloma; neoplasm cells; Oligoribonucleotides, Antisense - metabolism; Oriental traditional medicine; Research Paper; RNA, Messenger - metabolism; seed sequence; signal transduction; Signal Transduction - drug effects; signaling pathway; signaling pathway; multiple myeloma; mir-99a∼125b cluster; seed sequence; bioinformatics; berberine
• ISSN: 1547-6286; 1555-8584; 1555-8584
• DOI: 10.1080/15476286.2015.1017219

Background: Berberine (BBR) is a natural alkaloid derived from a traditional Chinese herbal medicine. However, the exact mechanisms underlying the different effects of berberine on MM cells have not been fully elucidated. Methods: A systematic analysis assay integrated common signaling pathways modulated by the 3 miRNA clusters and mRNAs in MM cells after BBR treatment. The role of the mir-99a∼125b cluster, an important oncomir in MM, was identified by comparing the effects of t-anti-mirs with complete complementary antisense locked nucleic acids (LNAs) against mature mir-125b (anti-mir-125b). Results: Three miRNAs clusters (miR-99a∼125b, miR-17∼92 and miR-106∼25) were significantly down-regulated in BBR-treated MM cells and are involved in multiple cancer-related signaling pathways. Furthermore, the top 5 differentially regulated genes, RAC1, NFκB1, MYC, JUN and CCND1 might play key roles in the progression of MM. Systematic integration revealed that 3 common signaling pathways (TP53, Erb and MAPK) link the 3 miRNA clusters and the 5 key mRNAs. Meanwhile, both BBR and seed-targeting t-anti-mir-99a∼125b cluster LNAs significantly induced apoptosis, G2-phase cell cycle arrest and colony inhibition. Conclusions: our results suggest that BBR suppresses multiple myeloma cells, partly by down-regulating the 3 miRNA clusters and many mRNAs, possibly through TP53, Erb and MAPK signaling pathways. The mir-99a∼125b cluster might be a novel target for MM treatment. These findings provide new mechanistic insight into the anticancer effects of certain traditional Chinese herbal medicine compounds.