TY - JOUR
T1 - MicroRNA MIR21 (miR-21) and PTGS2 expression in colorectal cancer and patient survival
AU - Mima, Kosuke
AU - Nishihara, Reiko
AU - Yang, Juhong
AU - Dou, Ruoxu
AU - Masugi, Yohei
AU - Shi, Yan
AU - Silva, Annacarolina Da
AU - Cao, Yin
AU - Song, Mingyang
AU - Nowak, Jonathan
AU - Gu, Mancang
AU - Li, Wanwan
AU - Morikawa, Teppei
AU - Zhang, Xuehong
AU - Wu, Kana
AU - Baba, Hideo
AU - Giovannucci, Edward L.
AU - Meyerhardt, Jeffrey A.
AU - Chan, Andrew T.
AU - Fuchs, Charles S.
AU - Qian, Zhi Rong
AU - Ogino, Shuji
N1 - Publisher Copyright:
© 2016 AACR.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84979992948
U2 - 10.1158/1078-0432.CCR-15-2173
DO - 10.1158/1078-0432.CCR-15-2173
M3 - Article
C2 - 26957558
AN - SCOPUS:84979992948
SN - 1078-0432
VL - 22
SP - 3841
EP - 3848
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -