title: MicroRNA MIR21 (miR-21) and PTGS2 Expression in Colorectal Cancer and Patient Survival.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mima
authors.affiliation: 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.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Juhong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Ruoxu
authors.initials: R
authors.lastname: Dou
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Masugi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Annacarolina
authors.initials: A
authors.lastname: da Silva
authors.affiliation: 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.
authors.forename: Yin
authors.initials: Y
authors.lastname: Cao
authors.affiliation: 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.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Song
authors.affiliation: Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Nowak
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Mancang
authors.initials: M
authors.lastname: Gu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Wanwan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Xuehong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Kana
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.affiliation: 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.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.affiliation: 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.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: 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.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.affiliation: 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.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human