title: 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.
abstract: 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.
authors.affiliation: a Department of Biochemistry and Molecular Biology; Medical College of Jinan University ; Guangzhou , China.
authors.forename: Maoxiao
authors.initials: M
authors.lastname: Feng
authors.forename: Xiaochuang
authors.initials: X
authors.lastname: Luo
authors.forename: Chunming
authors.initials: C
authors.lastname: Gu
authors.forename: Yumin
authors.initials: Y
authors.lastname: Li
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Zhu
authors.forename: Jia
authors.initials: J
authors.lastname: Fei
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D001599:Berberine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D020320:Oligoribonucleotides, Antisense / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000470:Alkaloids; C531888:MIRN125 microRNA, human; C561679:MIRN99 microRNA, human; D035683:MicroRNAs; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D001599:Berberine
keywords: berberine; bioinformatics; mir-99a∼125b cluster; multiple myeloma; seed sequence; signaling pathway
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