Data from MicroRNA <i>MIR21</i> (miR-21) and PTGS2 Expression in Colorectal Cancer and Patient Survival

Abstract

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