title: Epigenetic silencing of microRNA-34b/c plays an important role in the pathogenesis of malignant pleural mesothelioma.
abstract: OBJECTIVE
  Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Unlike other malignancies, TP53 mutations are rare in MPM. Recent studies have showed that altered expression of microRNA (miRNA) is observed in human malignant tumors. In this study, we investigated the alterations of miR-34s, a direct transcriptional target of TP53, and the role of miR-34s on the pathogenesis of MPM.
  
  
  METHODS
  Aberrant methylation and expression of miR-34s were examined in MPM cell lines and tumors. miR-34b/c was transfected to MPM cells to estimate the protein expression, cell proliferation, invasion, and cell cycle.
  
  
  RESULTS
  Aberrant methylation was present in 2 (33.3%) of 6 MPM cell lines and 13 (27.7%) of 47 tumors in miR-34a and in all 6 MPM cell lines (100%) and 40 (85.1%) of 47 tumors in miR-34b/c. Expression of miR-34a and 34b/c in all methylated cell lines was reduced and restored with 5-aza-2'-deoxycytidine treatment. Because epigenetic silencing was the major event in miR-34b/c, we investigated the functional role of miR-34b/c in MPM. miR-34b/c-transfected MPM cells with physiologic miR-34b/c expression exhibited antiproliferation with G(1) cell cycle arrest and suppression of migration, invasion, and motility. The forced overexpression of miR-34b/c, but not p53, showed a significant antitumor effect with the induction of apoptosis in MPM cells.
  
  
  CONCLUSIONS
  We show that the epigenetic silencing of miR-34b/c by methylation is a crucial alteration and plays an important role in the tumorigenesis of MPM, suggesting potential therapeutic options for MPM.
authors.affiliation: Departments of Cancer and Thoracic Surgery, Cell Biology, Gastroenterological Surgery, Transplant, and Surgical oncology, Urology, and Cellular Physiology, Okayama, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kubo
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyooka
authors.forename: Kazunori
authors.initials: K
authors.lastname: Tsukuda
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
authors.forename: Takuya
authors.initials: T
authors.lastname: Fukazawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Soh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Asano
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ueno
authors.forename: Takayuki
authors.initials: T
authors.lastname: Muraoka
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Nasu
authors.forename: Takumi
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.forename: Hideki
authors.initials: H
authors.lastname: Matsui
authors.forename: Nam-Ho
authors.initials: NH
authors.lastname: Huh
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Miyoshi
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D006801:Humans; D008654:Mesothelioma / Q000235:genetics; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D010997:Pleural Neoplasms / Q000235:genetics; D034622:RNA Interference; D014162:Transfection
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs