title: Mechanisms of colitis-accelerated colon carcinogenesis and its prevention with the combination of aspirin and curcumin: Transcriptomic analysis using RNA-seq.
abstract: Colorectal cancer (CRC) remains the leading cause of cancer-related death in the world. Aspirin (ASA) and curcumin (CUR) are widely investigated chemopreventive candidates for CRC. However, the precise mechanisms of their action and their combinatorial effects have not been evaluated. The purpose of the present study was to determine the effect of ASA, CUR, and their combination in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-accelerated colorectal cancer (CAC). We also aimed to characterize the differential gene expression profiles in AOM/DSS-induced tumors as well as in tumors modulated by ASA and CUR using RNA-seq. Diets supplemented with 0.02% ASA, 2% CUR or 0.01% ASA+1% CUR were given to mice from 1week prior to the AOM injection until the experiment was terminated 22weeks after AOM initiation. Our results showed that CUR had a superior inhibitory effect in colon tumorigenesis compared to that of ASA. The combination of ASA and CUR at a lower dose exhibited similar efficacy to that of a higher dose of CUR at 2%. RNA isolated from colonic tissue from the control group and from tumor samples from the experimental groups was subjected to RNA-seq. Transcriptomic analysis suggested that the low-dose combination of ASA and CUR modulated larger gene sets than the single treatment. These differentially expressed genes were situated in several canonical pathways important in the inflammatory network and liver metastasis in CAC. We identified a small subset of genes as potential molecular targets involved in the preventive action of the combination of ASA and CUR. Taken together, the current results provide the first evidence in support of the chemopreventive effect of a low-dose combination of ASA and CUR in CAC. Moreover, the transcriptional profile obtained in our study may provide a framework for identifying the mechanisms underlying the carcinogenesis process from normal colonic tissue to tumor development as well as the cancer inhibitory effects and potential molecular targets of ASA and CUR.
authors.affiliation: Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan City 32023, Taiwan.
authors.forename: Zheng-Yuan
authors.initials: ZY
authors.lastname: Su
authors.affiliation: Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Chengyue
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Gaspar
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Shanghai Roche Pharmaceuticals Ltd, Shanghai 10020, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Hart
authors.affiliation: Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Verzi
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. Electronic address: kongt@pharmacy.rutgers.edu.
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
mesh_terms: D000818:Animals; D001241:Aspirin / Q000008:administration & dosage*; D003092:Colitis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D003474:Curcumin / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D020869:Gene Expression Profiling / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D017423:Sequence Analysis, RNA / Q000379:methods*
chemical_list: D003474:Curcumin; D001241:Aspirin
keywords: Aspirin; Colitis-associated colorectal cancer; Curcumin; RNA-seq