Advertisement

Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression: An NRG Oncology/Gynecologic Oncology Group study

Published:September 29, 2017DOI:https://doi.org/10.1016/j.ygyno.2017.09.025

      Highlights

      • 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.

      Abstract

      Objective

      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.

      Methods

      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.

      Results

      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.

      Conclusions

      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.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Gynecologic Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. Cancer Facts and Figures 2014.
        • Plataniotis G.
        • Castiglione M.
        Endometrial cancer: EMSO clinical practice guidelines for diagnosis, treatment and follow-up.
        Ann. Oncol. 2010; 21: v41-v45
        • Orang A.V.
        • Safaralizadeh R.
        • Kazemzadeh-Bavili M.
        Mechanisms of miRNA-mediated gene regulation from common downregulation to mRNA-specific upregulation.
        Int. J. Genomics. 2014; 970607
        • Di Lava G.
        • Garofalo M.
        • Croce C.M.
        MicroRNAs in cancer.
        Annu. Rev. Pathol. 2014; 9: 287-314
        • Devor E.J.
        • Goodheart M.J.
        • Leslie K.K.
        Towards a microRNA signature of endometrial cancer.
        Proc. Obstet. Gynecol. 2011; 2: 2
        • Devor E.J.
        • Schickling B.M.
        • Leslie K.K.
        MicroRNA expression patterns across seven cancers are highly correlated and dominated by evolutionarily ancient families.
        Biomed. Rep. 2014; 2: 384-387
        • Li S.
        • Zhang J.
        • Wan X.
        Role of miRNAs in endometrial cancer.
        Histol. Histopathol. 2015; 30: 539-548
        • Devor E.J.
        • Hovey A.M.
        • Goodheart M.J.
        • Ramachandran S.
        • Leslie K.K.
        microRNA expression profiling of endometrial endometrioid adenocarcinomas and serous adenocarcinomas reveals profiles containing shared, unique and differentiating groups of microRNAs.
        Oncol. Rep. 2011; 26: 995-1002
        • Devor E.J.
        • DeMik J.N.
        • Ramachandran S.
        • Goodheart M.J.
        • Leslie K.K.
        Global dysregulation of the chromosome 14q32 imprinted region in uterine carcinosarcoma.
        Exp. Ther. Med. 2012; 3: 677-682
        • Schroeder A.
        • Mueller O.
        • Stocker S.
        • Salowsky R.
        • Leiber M.
        • Gassmann M.
        • et al.
        The RIN: an RNA integrity number for assigning integrity values to RNA measurements.
        BMC Mol. Biol. 2006; 7: 3
        • Livak K.J.
        • Schmittgen T.D.
        Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method.
        Methods. 2001; 25: 402-408
        • Schmittgen T.D.
        • Livak K.J.
        Analyzing real-time PCR data by the comparative Ct method.
        Nat. Protoc. 2008; 3: 1101-1108
        • Snedecor G.W.
        • Cochran W.G.
        Statistical Methods.
        8th edition. Iowa State University Press, Ames, Iowa1989
        • Abdi H.
        Bonferroni and Sidak corrections for multiple comparisons.
        in: Salkind N.J. Encyclopedia of Measurement and Statistics. Sage, Thousand Oaks, CA2007: 9
        • Dweep H.
        • Sticht C.
        • Pandey P.
        • Gretz N.
        miRWalk - database: prediction of possible miRNA binding sites by "walking" the genes of 3 genomes.
        J. Biomed. Inform. 2011; 44: 839-7
        • Huang da W.
        • Sherman B.T.
        • Lempicki R.A.
        Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists.
        Nucleic Acids Res. 2009; 37: 1-13
        • Huang da W.
        • Sherman B.T.
        • Lempicki R.A.
        Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.
        Nat. Protoc. 2009; 4: 44-57
        • Albitar L.
        • Pickett G.
        • Morgan M.
        • Davies S.
        • Leslie K.K.
        Models representing type I and type II human endometrial cancers: Ishikawa H and Hec50co cells.
        Gynecol. Oncol. 2007; 106: 52-64
        • Korch C.
        • Spillman M.A.
        • Jackson T.A.
        • Jacobsen B.M.
        • Murphey S.K.
        • Lessey B.A.
        • et al.
        DNA profile analysis of endometrial and ovarian cell lines reveals misidentification, redundancy and contamination.
        Gynecol. Oncol. 2012; 127: 241-248
        • O'Neill C.F.
        • Urs S.
        • Cinelli C.
        • Lincoln A.
        • Nadeau R.J.
        • Leon R.
        • et al.
        Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth.
        Am. J. Pathol. 2007; 171: 1023-1036
        • Storey J.D.
        • Tibshirani R.
        Statistical significance for genome wide studies.
        Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 9440-9445
        • The Cancer Genome Atlas Research Network
        Integrated genomic characterization of endometrial carcinoma.
        Nature. 2013; 497: 67-73
        • Espinoza I.
        • Miele L.
        Notch inhibitors for cancer treatment.
        Pharmacol. Ther. 2013; 139: 95-110
        • Hashimoto Y.
        • Akiyama Y.
        • Otsubo T.
        • Shimada S.
        • Yuasa Y.
        Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis.
        Carcinogenesis. 2010; 31: 777-784
        • Ayala-Ortega E.
        • Arzate-Mejia R.
        • Perez-Molina R.
        • Gonzalez-Buendia E.
        • Meier K.
        • Guerrero G.
        • Recillas-Targa F.
        Epigenetic silencing of miR-181c by DNA methylation in glioblastoma cell lines.
        BMC Cancer. 2016; 16: 226
        • Morice P.
        • Leary A.
        • Creutzberg C.
        • Abu-Rustum N.
        • Darai E.
        Endometrial cancer.
        Lancet. 2015; https://doi.org/10.1016/S0140-6736(15)00130-0
        • Artavanis-Tsakonas S.
        • Rand M.D.
        • Lake R.J.
        Notch signaling: cell fate control and signal integration in development.
        Science. 1999; 284: 770-776
        • Dill M.T.
        • Tornillo L.
        • Fritzius T.
        • Terracciano L.
        • Semela D.
        • Bettler B.
        • et al.
        Constitutive Notch2 signaling induces hepatic tumors in mice.
        Hepatology. 2013; 57: 1607-1619
        • Chen L.
        • Chen X.R.
        • Zhang R.
        • Li P.
        • Liu Y.
        • Yan K.
        • et al.
        MicroRNA-107 inhibits glioma cell migration and invasion by modulating NOTCH2 expression.
        J. Neuro-Oncol. 2013; 112: 59-66
        • Li J.
        • Ding S.
        • Ying L.
        • Hu A.
        • Hu Y.
        • Liang X.
        Effect of siRNA-mediated silencing of Notch2 on proliferation of the HepG2 human hepatocellular carcinoma cells.
        Zhonghua Gan Zang Bing Za Zhi. 2014; 22: 354-357
        • Okuhashi Y.
        • Itoh M.
        • Nara N.
        • Tohda S.
        NOTCH knockdown affects the proliferation and mTOR signaling of leukemia cells.
        Anticancer Res. 2013; 33: 4293-4298
        • Tseng Y.C.
        • Tsai Y.H.
        • Tseng M.J.
        • Hsu K.W.
        • Yang M.C.
        • Huang K.H.
        • et al.
        Notch2-induced COX-2 expression enhancing gastric cancer progression.
        Mol. Carcinog. 2012; 51: 939-951
        • Sivasankaran B.
        • Degen M.
        • Ghaffari A.
        • Hegi M.E.
        • Hamou M.F.
        • Ionescu M.C.
        • et al.
        Tenascin-C is a novel RBP Jkappa-induced target gene for Notch signaling in gliomas.
        Cancer Res. 2009; 69: 458-465
        • Huijgens A.N.J.
        • Mertens H.J.M.M.
        Factors predicting recurrent endometrial cancer.
        FVV in ObGyn. 2013; 5: 179-186
        • Gnyszka A.
        • Jastrzebski Z.
        • Flis S.
        DNA methyltransferase inhibitors and their emerging Role in epigenetic therapy of cancer.
        Anticancer Res. 2013; 33: 2989-2996