Aspirin and the risk of colorectal cancer in relation to the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).
Aspirin use reduces the risk of colorectal neoplasia, at least in part, through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2)-related pathways. Hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (15-PGDH, HPGD) is down-regulated in colorectal cancers and functions as a metabolic antagonist of PTGS2. We hypothesized that the effect of aspirin may be antagonized by low 15-PGDH expression in the normal colon. In the Nurses' Health Study and the Health Professionals Follow-Up Study, we collected data on aspirin use every 2 years and followed up participants for diagnoses of colorectal cancer. Duplication-method Cox proportional, multivariable-adjusted, cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for incident colorectal cancer according to 15-PGDH mRNA expression level measured in normal mucosa from colorectal cancer resections. Among 127,865 participants, we documented 270 colorectal cancer cases from which we could assess 15-PGDH expression. Compared with nonuse, regular aspirin use was associated with lower risk of colorectal cancer that developed within a background of colonic mucosa with high 15-PGDH expression [multivariable HR, 0.49; 95% confidence interval (CI), 0.34 to 0.71], but not with low 15-PGDH expression (multivariable HR, 0.90; 95% CI, 0.63 to 1.27) (P for heterogeneity = 0.018). Regular aspirin use was associated with lower incidence of colorectal cancers arising in association with high 15-PGDH expression, but not with low 15-PGDH expression in normal colon mucosa. This suggests that 15-PGDH expression level in normal colon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention.
Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals Case Medical Center, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Stephen P
SP
Fink
Mai
M
Yamauchi
Reiko
R
Nishihara
Seungyoun
S
Jung
Aya
A
Kuchiba
Kana
K
Wu
Eunyoung
E
Cho
Edward
E
Giovannucci
Charles S
CS
Fuchs
Shuji
S
Ogino
Sanford D
SD
Markowitz
Andrew T
AT
Chan
D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D003710:Demography; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D015994:Incidence; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
D012333:RNA, Messenger; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D001241:Aspirin