title: Endobronchial miRNAs as biomarkers in lung cancer chemoprevention.
abstract: Lung cancers express lower levels of prostacyclin than normal lung tissues. Prostacyclin prevents lung cancer in a variety of mouse models. A randomized phase II trial comparing oral iloprost (a prostacyclin analog) with placebo in high-risk subjects showed improvement in bronchial histology in former, but not current, smokers. This placebo-controlled study offered the opportunity for investigation of other potential intermediate endpoint and predictive biomarkers to incorporate into chemoprevention trials. Matched bronchial biopsies were obtained at baseline and at 6-month follow-up from 125 high-risk individuals who completed the trial: 31/29 and 37/28 current/former smokers in the iloprost and placebo arm, respectively. We analyzed the expression of 14 selected miRNAs by Real Time PCR in 496 biopsies. The expression of seven miRNAs was significantly correlated with histology at baseline. The expression of miR-34c was inversely correlated with histology at baseline (P < 0.0001) and with change in histology at follow-up (P = 0.0003), independent of treatment or smoking status. Several miRNAs were also found to be differentially expressed in current smokers as compared with former smokers. In current smokers, miR-375 was upregulated at baseline (P < 0.0001) and downregulated after treatment with iloprost (P = 0.0023). No miRNA at baseline reliably predicted a response to iloprost. No biomarker predictive of response to iloprost was found. MiR-34c was inversely correlated with baseline histology and with histology changes. Mir-34c changes at follow-up could be used as a quantitative biomarker that parallels histologic response in formalin-fixed bronchial biopsies in future lung cancer chemoprevention studies.
authors.affiliation: Department of Medicine, Division of Medical Oncology, Colorado School of Public Health, Aurora, 80045, USA. celinejmmascaux@gmail.com
authors.forename: Celine
authors.initials: C
authors.lastname: Mascaux
authors.forename: William J
authors.initials: WJ
authors.lastname: Feser
authors.forename: Marina T
authors.initials: MT
authors.lastname: Lewis
authors.forename: Anna E
authors.initials: AE
authors.lastname: Barón
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Coldren
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Merrick
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Kennedy
authors.forename: John I
authors.initials: JI
authors.lastname: Eckelberger
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Rozeboom
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: York E
authors.initials: YE
authors.lastname: Miller
authors.forename: Robert L
authors.initials: RL
authors.lastname: Keith
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001980:Bronchi / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D018890:Chemoprevention; D006801:Humans; D016285:Iloprost / Q000008:administration & dosage / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010919:Placebos; D012907:Smoking / Q000009:adverse effects / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D035683:MicroRNAs; D010919:Placebos; D016285:Iloprost