CYP24A1 is an independent prognostic marker of survival in patients with lung adenocarcinoma.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Guoan Chen, So Hee Kim, Amanda N King, Lili Zhao, Robert U Simpson, Paul J Christensen, Zhuwen Wang, Dafydd G Thomas, Thomas J Giordano, Lin Lin, Dean E Brenner, David G Beer, Nithya Ramnath
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 4 Pg. 817-26 (Feb 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21169243 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2010 AACR.

Chemical References

• Cytostatic Agents
• RNA, Messenger
• Receptors, Calcitriol
• Steroid Hydroxylases
• CYP24A1 protein, human
• Vitamin D3 24-Hydroxylase
• Calcitriol

Topics

• Adenocarcinoma (genetics, mortality, pathology)
• Calcitriol (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytostatic Agents (pharmacology)
• Genetic Association Studies
• Humans
• Kaplan-Meier Estimate
• Lung Neoplasms (genetics, mortality, pathology)
• RNA, Messenger (metabolism)
• Receptors, Calcitriol (genetics, metabolism)
• Steroid Hydroxylases (genetics, metabolism)
• Up-Regulation
• Vitamin D3 24-Hydroxylase