title: Functional analysis of miR-34c as a putative tumor suppressor in high-grade serous ovarian cancer.
abstract: Altered microRNA expression patterns are implicated in the formation of many human diseases, including ovarian cancer. Our laboratory previously created Dicer(fl/fl)/Pten(fl/fl)/Amhr2(cre/+) mice, which developed high-grade serous carcinomas originating from mouse fallopian tubes, while neither Dicer(fl/fl)/Amhr2(cre/+) nor Pten(fl/fl)/Amhr2(cre/+) mice developed tumors. To explore miRNAs involved in the tumorigenesis in the double-knockout (DKO) mice, tumor cell lines were established from mouse primary tumors, and the most abundant miRNAs present in mouse normal fallopian tubes, let-7b and miR-34c, were expressed in these cell lines. We found that miR-34c had a more dramatic effect on inhibiting tumor cell viability than let-7b. The action of miR-34c induced tumor cell cycle arrest in G1 phase and apoptosis, and was accompanied with the regulation of key genes involved in cell proliferation and cell cycle G1/S transition. miR-34c suppressed the expression of Ezh2 and Mybl2, which may transcriptionally and functionally activate Cdkn1c. Furthermore, miR-34c levels are extremely low in human serous adenocarcinomas compared with human normal fallopian tubes. Expression of miR-34c in human ovarian cancer cells phenocopied its effects in DKO mouse tumor cells. However, miR-34b/c(-/-)/Pten(fl/fl)/Amhr2(cre/+) mice failed to develop high-grade serous carcinomas, implicating a combination of miRNAs in the tumorigenesis process. Thus, while miR-34c is a putative tumor suppressor in high-grade serous ovarian carcinoma with potential therapeutic advantages, screening of additional miRNAs for their effects alone and in combination with miR-34c is highly warranted to uncover miRNAs that synergize with miR-34c against cancer.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas zhifengy@bcm.edu.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
authors.forename: Jaeyeon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California.
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas Department of Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas Department of Biology and Biochemistry, University of Houston, Houston, Texas.
authors.forename: Preethi H
authors.initials: PH
authors.lastname: Gunaratne
authors.affiliation: Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas Department of Pharmacology, Baylor College of Medicine, Houston, Texas.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Hawkins
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas Department of Pharmacology, Baylor College of Medicine, Houston, Texas Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas mmatzuk@bcm.edu.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Matzuk
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology; D053487:DEAD-box RNA Helicases / Q000235:genetics; D005187:Fallopian Tubes; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C408087:DICER1 protein, human; D043244:Ribonuclease III; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D053487:DEAD-box RNA Helicases
keywords: Dicer/Pten double knockout; miR-34b/c/Pten double knockout; microRNA; ovarian cancer