title: miR-125b inhibitor may enhance the invasion-prevention activity of temozolomide in glioblastoma stem cells by targeting PIAS3.
abstract: BACKGROUND
  Temozolomide, an alkylating agent, is a promising chemotherapeutic agent for treating glioblastoma. Although chemotherapy with temozolomide may restrain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells maintaining these tumors persist. Previous research has shown that temozolomide can inhibit the proliferation of human glioblastoma stem cells (GSCs); however, no research has focused on the invasion of GSCs, which is an important factor for glioblastoma recurrence. Accumulating evidence indicates that microRNA (miR)-125b over-expression in GSCs may increase their invasiveness.
  
  
  OBJECTIVE
  Our objective was to identify the effects and mechanism of action of an miR-125b inhibitor combined with temozolomide in the invasive pathogenesis of GSCs.
  
  
  METHODS
  We modified the levels of miR-125b expression in primary GSCs in order to observe the effect on sensitivity to temozolomide on invasion, and we further analyzed the differences in mechanism between miR-125b treatment alone and treatment with miR-125b plus temozolomide using the Cancer PathwayFinder PCR Array.
  
  
  RESULTS
  Our results demonstrated that either an miR-125b inhibitor or temozolomide could modestly inhibit the invasiveness of GSCs. Furthermore, GSCs that were pre-transfected with an miR-125b inhibitor, then treated with temozolomide, showed significantly decreased invasiveness when compared with GSCs treated with an miR-125b inhibitor or temozolomide alone. Further research into the underlying mechanism demonstrated that the miR-125b inhibitor enhanced the invasion-prevention activity of temozolomide in GSCs through targeting PIAS3 (protein inhibitor of activated STAT [signal transducer and activator of transcription]), which contributed to reduced STAT3 transcriptional activity and subsequent decreased expression of matrix metalloproteinase (MMP)-2 and -9.
  
  
  CONCLUSIONS
  miR-125b could play a role in the development of temozolomide resistance in GSCs. Inhibition of miR-125b expression may enhance sensitivity of GSCs to temozolomide by targeting PIAS3 on cell invasion.
authors.affiliation: Department of Neurosurgery, The First People's Hospital of Kunshan affiliated with Jiangsu University, Suzhou, 215300, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Yi
authors.initials: Y
authors.lastname: Wan
authors.forename: Guan
authors.initials: G
authors.lastname: Sun
authors.forename: Shuguang
authors.initials: S
authors.lastname: Zhang
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Wang
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zeng
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077204:Temozolomide
chemical_list: C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D034741:RNA, Small Interfering; D003606:Dacarbazine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000077204:Temozolomide