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| Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2020 Dec 14. pii: 1055-9965.EPI-20-1176. doi: 10.1158/1055-9965.EPI-20-1176 |
| A combined proteomics and Mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer. |
| Nounu A1, Greenhough A2, Heesom KJ3, Richmond RC4, Zheng J5, Weinstein SJ6, Albanes D7, Baron JA8, Hopper JL9, Figueiredo JC10, Newcomb PA11, Lindor NM12, Casey G13, Platz EA14, Le Marchand L15, Ulrich CM16, Li CI17, van Duijnhoven FJB18, Gsur A19, Campbell P20, Moreno V21, Vodicka P22, Vodickova L23, Brenner H24, Chang-Claude J25, Hoffmeister M26, Sakoda LC27, Slattery ML28, Schoen RE29, Gunter MJ30, Castellví-Bel S31, Kim HR32, Kweon SS33, Chan AT34, Li L35, Zheng W36, Bishop DT37, Buchanan DD38, Giles GG39, Gruber SB40, Rennert G41, Stadler ZK42, Harrison TA43, Lin Y44, Keku TO45, Woods MO46, Schafmayer C47, Van Guelpen B48, Gallinger S49, Hampel H50, Berndt SI51, Pharoah PDP52, Lindblom A53, Wolk A54, Wu AH55, White E56, Peters U57, Drew DA58, Scherer D59, Bermejo JL60, Williams AC61, Relton CL62 |
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Abstract BACKGROUND: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. METHODS: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labelling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N=3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N=31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). RESULTS: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2 and ARFIP2 expression and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR:1.08, 95% CI:1.03-1.13, OR:3.33, 95% CI:2.46-4.50 and OR:1.15, 95% CI:1.02-1.29, respectively). CONCLUSIONS: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation indicating a possible role in aspirin's reduction of metastasis. IMPACT: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk. |
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Copyright ©2020, American Association for Cancer Research. |
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Publikations ID: 33318029 Quelle: öffnen |
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