title: CYP24A1 is an independent prognostic marker of survival in patients with lung adenocarcinoma.
abstract: OBJECTIVE
  The active form of vitamin D, 1α,25-dihydroxyvitamin D(3) (1,25-D(3)), exerts antiproliferative effects in cancers, including lung adenocarcinoma (AC). CYP24A1 is overexpressed in many cancers and encodes the enzyme that catabolizes 1,25-D(3). The purpose of our study was to assess CYP24A1 as a prognostic marker and to study its relevance to antiproliferative activity of 1,25-D(3) in lung AC cells.
  
  
  METHODS
  Tumors and corresponding normal specimens from 86 patients with lung AC (stages I-III) were available. Affymetrix array data and subsequent confirmation by quantitative real time-PCR were used to determine CYP24A1 mRNA expression. A subsequent validation set of 101 lung AC was used to confirm CYP24A1 mRNA expression and its associations with clinical variables. The antiproliferative effects of 1,25-D(3) were examined using lung cancer cell lines with high as well as low expression of CYP24A1 mRNA.
  
  
  RESULTS
  CYP24A1 mRNA was elevated 8- to 50-fold in lung AC (compared to normal nonneoplastic lung) and significantly higher in poorly differentiated cancers. At 5 years of follow-up, the probability of survival was 42% (high CYP24A1, n = 29) versus 81% (low CYP24A1, n = 57) (P = 0.007). The validation set of 101 tumors showed that CYP24A1 was independently prognostic of survival (multivariate Cox model adjusted for age, gender, and stage, P = 0.001). A549 cells (high CYP24A1) were more resistant to antiproliferative effects of 1,25-D(3) compared with SKLU-1 cells (low CYP24A1).
  
  
  CONCLUSIONS
  CYP24A1 overexpression is associated with poorer survival in lung AC. This may relate to abrogation of antiproliferative effects of 1,25-D(3) in high CYP24A1 expressing lung AC.
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Guoan
authors.initials: G
authors.lastname: Chen
authors.forename: So Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Amanda N
authors.initials: AN
authors.lastname: King
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.forename: Robert U
authors.initials: RU
authors.lastname: Simpson
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Christensen
authors.forename: Zhuwen
authors.initials: Z
authors.lastname: Wang
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Giordano
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Dean E
authors.initials: DE
authors.lastname: Brenner
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
authors.forename: Nithya
authors.initials: N
authors.lastname: Ramnath
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D002117:Calcitriol / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054697:Cytostatic Agents / Q000494:pharmacology; D056726:Genetic Association Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D054697:Cytostatic Agents; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol