Abstract
Long-term use of aspirin is associated with lower risk of colorectal cancer and other cancers; however, the mechanism of chemopreventive effect of aspirin is not fully understood. Animal studies suggest that COX-2, NFκB signaling and Wnt/β-catenin pathways may play a role, but no clinical trials have systematically evaluated the biological response to aspirin in healthy humans. Using a high-density antibody array, we assessed the difference in plasma protein levels after 60 days of regular dose aspirin (325 mg/day) compared to placebo in a randomized double-blinded crossover trial of 44 healthy non-smoking men and women, aged 21–45 years. The plasma proteome was analyzed on an antibody microarray with ~3,300 full-length antibodies, printed in triplicate. Moderated paired t-tests were performed on individual antibodies, and gene-set analyses were performed based on KEGG and GO pathways. Among the 3,000 antibodies analyzed, statistically significant differences in plasma protein levels were observed for nine antibodies after adjusting for false discoveries (FDR adjusted p-value<0.1). The most significant protein was succinate dehydrogenase subunit C (SDHC), a key enzyme complex of the mitochondrial tricarboxylic acid (TCA) cycle. The other statistically significant proteins (NR2F1, MSI1, MYH1, FOXO1, KHDRBS3, NFKBIE, LYZ and IKZF1) are involved in multiple pathways, including DNA base-pair repair, inflammation and oncogenic pathways. None of the 258 KEGG and 1,139 GO pathways was found to be statistically significant after FDR adjustment. This study suggests several chemopreventive mechanisms of aspirin in humans, which have previously been reported to play a role in anti- or pro-carcinogenesis in cell systems; however, larger, confirmatory studies are needed.
Highlights
Low-dose and regular-strength aspirin use is consistently observed to be associated with reduced long-term risk of colorectal cancer (CRC) risk of adenomatous polyps, pre-cancerous lesions that increase risk of CRC [1, 2]
A genome-wide investigation of gene-environment interactions reported that the association of non-steroidal anti-inflammatory drugs (NSAIDs) with CRC risk differed according to genetic variation at 2 SNPs [13]; these are related to genes involved in activation of the PI3K signaling pathway
The most significant protein was succinate dehydrogenase subunit C (SDHC), with an average 34% lower expression level on aspirin than placebo (p-value = 4.47×10−05; false discovery rate (FDR)-adjusted p-value = 0.06)
Summary
Low-dose and regular-strength aspirin use is consistently observed to be associated with reduced long-term risk of colorectal cancer (CRC) risk of adenomatous polyps, pre-cancerous lesions that increase risk of CRC [1, 2]. Aspirin has been shown to inhibit the oncogenic Wnt/β-catenin pathway [8] and the extracellular-signalregulated kinase (ERK) signaling pathway [9] in colon cancer cell lines. Indirect support for these pathways from human studies comes from nested case-control studies which suggest that interactions between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and polymorphisms in oncogenes in the Wnt/β-catenin signaling pathway [10] and NFкB-signaling pathway [11] modify CRC risk [12]. Other pathways related to transcription factors, cell proliferation and apoptosis have been suggested [14]
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