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Clin Cancer Res. 2016 Aug 1;22(15):3841-8. doi: 10.1158/1078-0432.CCR-15-2173. Epub 2016 Mar 8.

MicroRNA MIR21 (miR-21) and PTGS2 Expression in Colorectal Cancer and Patient Survival.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
2
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
3
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
4
Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
5
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
6
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
7
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
8
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan.
9
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
10
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts.
11
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
12
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. shuji_ogino@dfci.harvard.edu.

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. Clin Cancer Res; 22(15); 3841-8. ©2016 AACR.

PMID:
26957558
PMCID:
PMC4970894
DOI:
10.1158/1078-0432.CCR-15-2173
[Indexed for MEDLINE]
Free PMC Article

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