MicroRNA MIR21 (miR-21) and PTGS2 expression in colorectal cancer and patient survival

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. FuchsZhi Rong Qian, Shuji Ogino

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)3841-3848
Number of pages8
JournalClinical Cancer Research
Volume22
Issue number15
DOIs
Publication statusPublished - 2016 Aug 1
Externally publishedYes

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Cyclooxygenase 2
MicroRNAs
Colorectal Neoplasms
Survival
Neoplasms
Dinoprostone
Microsatellite Instability
CpG Islands
Tumor Microenvironment
Mortality
Health
Prostaglandin-Endoperoxide Synthases
Rectal Neoplasms
Survival Analysis
Proportional Hazards Models
Colonic Neoplasms
Methylation
Aspirin
Reverse Transcription
Immunity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

MicroRNA MIR21 (miR-21) and PTGS2 expression in colorectal cancer and patient survival. / Mima, Kosuke; Nishihara, Reiko; Yang, Juhong; Dou, Ruoxu; Masugi, Yohei; Shi, Yan; Silva, Annacarolina Da; Cao, Yin; Song, Mingyang; Nowak, Jonathan; Gu, Mancang; Li, Wanwan; Morikawa, Teppei; Zhang, Xuehong; Wu, Kana; Baba, Hideo; Giovannucci, Edward L.; Meyerhardt, Jeffrey A.; Chan, Andrew T.; Fuchs, Charles S.; Qian, Zhi Rong; Ogino, Shuji.

In: Clinical Cancer Research, Vol. 22, No. 15, 01.08.2016, p. 3841-3848.

Research output: Contribution to journalArticle

Mima, K, Nishihara, R, Yang, J, Dou, R, Masugi, Y, Shi, Y, Silva, AD, Cao, Y, Song, M, Nowak, J, Gu, M, Li, W, Morikawa, T, Zhang, X, Wu, K, Baba, H, Giovannucci, EL, Meyerhardt, JA, Chan, AT, Fuchs, CS, Qian, ZR & Ogino, S 2016, 'MicroRNA MIR21 (miR-21) and PTGS2 expression in colorectal cancer and patient survival', Clinical Cancer Research, vol. 22, no. 15, pp. 3841-3848. https://doi.org/10.1158/1078-0432.CCR-15-2173
Mima, Kosuke ; Nishihara, Reiko ; Yang, Juhong ; Dou, Ruoxu ; Masugi, Yohei ; Shi, Yan ; Silva, Annacarolina Da ; Cao, Yin ; Song, Mingyang ; Nowak, Jonathan ; Gu, Mancang ; Li, Wanwan ; Morikawa, Teppei ; Zhang, Xuehong ; Wu, Kana ; Baba, Hideo ; Giovannucci, Edward L. ; Meyerhardt, Jeffrey A. ; Chan, Andrew T. ; Fuchs, Charles S. ; Qian, Zhi Rong ; Ogino, Shuji. / MicroRNA MIR21 (miR-21) and PTGS2 expression in colorectal cancer and patient survival. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 15. pp. 3841-3848.
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abstract = "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.",
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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

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.

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