Aspirin and the risk of colorectal cancer in relation to the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).

Abstract

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.

• Authors: Stephen P Fink, Mai Yamauchi, Reiko Nishihara, Seungyoun Jung, Aya Kuchiba, Kana Wu, Eunyoung Cho, Edward Giovannucci, Charles S Fuchs, Shuji Ogino, Sanford D Markowitz, Andrew T Chan
• Journal: Science translational medicine (Sci Transl Med) Vol. 6 Issue 233 Pg. 233re2 (Apr 23 2014) ISSN: 1946-6242 [Electronic] United States
• PMID: 24760190 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Hydroxyprostaglandin Dehydrogenases
• 15-hydroxyprostaglandin dehydrogenase
• Aspirin

Topics

• Aspirin (pharmacology, therapeutic use)
• Colorectal Neoplasms (drug therapy, enzymology, genetics)
• Demography
• Female
• Gene Expression Regulation, Enzymologic (drug effects)
• Humans
• Hydroxyprostaglandin Dehydrogenases (genetics, metabolism)
• Incidence
• Intestinal Mucosa (enzymology, pathology)
• Male
• Middle Aged
• RNA, Messenger (genetics, metabolism)
• Risk Factors