title: miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer.
abstract: The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer. Functional screening of 327 synthetic miRNAs in an endometrial cancer cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer.
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Tsuruta
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Kozaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Uesugi
authors.forename: Mayuko
authors.initials: M
authors.lastname: Furuta
authors.forename: Akira
authors.initials: A
authors.lastname: Hirasawa
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Susumu
authors.forename: Daisuke
authors.initials: D
authors.lastname: Aoki
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D020756:Coatomer Protein / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D050699:E2F3 Transcription Factor / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D007438:Introns; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein
chemical_list: D002352:Carrier Proteins; D020756:Coatomer Protein; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; C550856:MIRN152 microRNA, human; D035683:MicroRNAs; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met