American Association for Cancer Research
10780432ccr152173-sup-155188_2_supp_data_3361270_q2nfqq.doc (108 kB)

Supplementary Methods from MicroRNA MIR21 (miR-21) and PTGS2 Expression in Colorectal Cancer and Patient Survival

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journal contribution
posted on 2023-03-31, 18:10 authored by Kosuke Mima, Reiko Nishihara, Juhong Yang, Ruoxu Dou, Yohei Masugi, Yan Shi, Annacarolina da Silva, Yin Cao, Mingyang Song, Jonathan Nowak, Mancang Gu, Wanwan Li, Teppei Morikawa, Xuehong Zhang, Kana Wu, Hideo Baba, Edward L. Giovannucci, Jeffrey A. Meyerhardt, Andrew T. Chan, Charles S. Fuchs, Zhi Rong Qian, Shuji Ogino

Assessment of aspirin use and statistical analysis to assess an interaction of tumor MIR21 expression level and regular aspirin use after diagnosis in survival analysis



Dana-Farber Cancer Institute

Bennett Family Fund

the Entertainment Industry Foundation

National Colorectal Cancer Research Alliance

Japan Society for the Promotion of Science



Purpose: Prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase-2; a target of aspirin) produces inflammatory mediator prostaglandin E2 (PGE2), and contributes to colorectal neoplasia development. PTGS2-driven inflammatory responses can induce tumor expression of microRNA MIR21 (miR-21) that can increase local PGE2 level by downregulating PGE2-metabolizing enzymes. We hypothesized that the prognostic association of tumor MIR21 expression level in colorectal carcinoma might depend on inflammatory tumor microenvironment and be stronger in tumors expressing high-level PTGS2.Experimental Design: Utilizing 765 rectal and colon cancer specimens in the Nurses' Health Study and the Health Professionals Follow-up Study, we measured MIR21 expression by quantitative reverse transcription PCR, and PTGS2 expression by immunohistochemistry. Cox proportional hazards regression model was used to assess statistical interaction between MIR21 and PTGS2 in colorectal cancer–specific survival analysis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation level, and KRAS, BRAF, and PIK3CA mutations.Results: Tumor MIR21 expression level was associated with higher colorectal cancer–specific mortality (Ptrend = 0.029), and there was a statistically significant interaction between MIR21 and PTGS2 (Pinteraction = 0.0004). The association between MIR21 expression and colorectal cancer–specific mortality was statistically significant in PTGS2-high cancers (multivariable hazard ratio of the highest vs. lowest quartile of MIR21, 2.28; 95% confidence interval, 1.42–3.67; Ptrend = 0.0004) but not in PTGS2-absent/low cancers (Ptrend = 0.22).Conclusions:MIR21 expression level in colorectal carcinoma is associated with worse clinical outcome, and this association is stronger in carcinomas expressing high-level PTGS2, suggesting complex roles of immunity and inflammation in tumor progression. Clin Cancer Res; 22(15); 3841–8. ©2016 AACR.