Journal article
Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression: An NRG Oncology/Gynecologic Oncology Group study
Gynecologic Oncology, Vol.147(3), pp.648-653
12/2017
DOI: 10.1016/j.ygyno.2017.09.025
PMCID: PMC5698180
PMID: 28969912
Abstract
•This study screened for miRNAs associated with endometrial cancer recurrence.•We profiled miRNAs from the three major endometrial cancer subtypes in GOG210.•One miRNA, miR-181c, was significantly dysregulated in recurrent tumors.•miR-181c was downregulated in recurrent endometrioid adenocarcinoma subtype.•Loss of miR-181c correlated with increased levels of its target NOTCH2. Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.
Details
- Title: Subtitle
- Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression: An NRG Oncology/Gynecologic Oncology Group study
- Creators
- Eric J Devor - Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, United StatesJeffrey Miecznikowski - Department of Biostatistics, SUNY University at Buffalo, United StatesBrandon M Schickling - Department of Internal Medicine, University of Iowa Carver College of Medicine, United StatesJesus Gonzalez-Bosquet - Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, United StatesHeather A Lankes - NRG Oncology Statistics and Data Management Center, Roswell Park Cancer Institute, United StatesPremal Thaker - Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine and Siteman Cancer Center, St. Louis, MO, United StatesPeter A Argenta - University of Minnesota School of Medicine, Minneapolis, MN, United StatesMichael L Pearl - Gynecologic Oncology, Stony Brook University Hospital, Stony Brook, NY, United StatesSusan L Zweizig - University of Massachusetts, United StatesRobert S Mannel - Gynecologic Oncology, Stephenson Oklahoma Cancer Center, Oklahoma City, OK, United StatesAmy Brown - Department of Gynecology/Oncology, Hospital of Central Connecticut, New Britain, CT 06050, USANilsa C Ramirez - The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, United StatesOlga B Ioffe - Department of Pathology, University of Maryland Medical Center, Baltimore, MD 21201, United StatesKay J Park - Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, United StatesWilliam T Creasman - Medical University of South Carolina, USC Women's Health Gynecology, Charleston, SC 29425, United StatesMichael J Birrer - Center for Cancer Research, The Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United StatesDavid Mutch - Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine and Siteman Cancer Center, St. Louis, MO, United StatesKimberly K Leslie - Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, United States
- Resource Type
- Journal article
- Publication Details
- Gynecologic Oncology, Vol.147(3), pp.648-653
- DOI
- 10.1016/j.ygyno.2017.09.025
- PMID
- 28969912
- PMCID
- PMC5698180
- NLM abbreviation
- Gynecol Oncol
- ISSN
- 0090-8258
- eISSN
- 1095-6859
- Publisher
- Elsevier Inc
- Grant note
- R01 CA099908; R01 CA184101; U10 CA180868; U10 CA180822; CA27469 U24CA114793; CA37517 / National Cancer Institute (http://dx.doi.org/10.13039/100000054) Department of Obstetrics and Gynecology Research Fund
- Language
- English
- Date published
- 12/2017
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9983930394802771
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