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 - Funding Information:
This work was supported by U.S. NIH grants (P01 CA87969 to M.J. Stampfer ∗ ; UM1 CA186107 to M.J. Stampfer ∗; P01 CA55075 to W.C. Willett ∗; UM1 CA167552 to W.C. Willett ∗; P50 CA127003 to C.S. Fuchs; R01 CA137178 to A.T. Chan.; R01 CA151993 to S. Ogino; R35 CA197735 to S. Ogino; and K07 CA190673 to R. Nishihara); and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. K. Mima is supported by a grant from Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from Japan Society for the Promotion of Science. ∗These grants support tissue collection in the Nurses' Health Study and the Health Professionals Follow-up Study. Because the authors used colorectal carcinoma tissue specimens from the Nurses' Health Study and the Health Professionals Follow-up Study, the information for these grants is included even though M.J. Stampfer and W.C. Willet are not listed authors. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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 - http://www.scopus.com/inward/record.url?scp=84979992948&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84979992948&partnerID=8YFLogxK
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 -
