title: ErbB2-intronic microRNA-4728: a novel tumor suppressor and antagonist of oncogenic MAPK signaling.
abstract: Although the role of the ErbB2/HER2 oncogene in cancers has been extensively studied, how ErbB2 is regulated remains poorly understood. A novel microRNA, mir-4728, was recently found within an intron of the ErbB2 gene. However, the function and clinical relevance of this intronic miRNA are completely unknown. Here, we demonstrate that mir-4728 is a negative regulator of MAPK signaling through directly targeting the ERK upstream kinase MST4 and exerts numerous tumor-suppressive properties in vitro and in animal models. Importantly, our patient sample study shows that mir-4728 was under-expressed in breast tumors compared with normal tissue, and loss of mir-4728 correlated with worse overall patient survival. These results strongly suggest that mir-4728 is a tumor-suppressive miRNA that controls MAPK signaling through targeting MST4, revealing mir-4728's significance as a potential prognostic factor and target for therapeutic intervention in cancer. Moreover, this study represents a conceptual advance by providing strong evidence that a tumor-suppressive miRNA can antagonize the canonical signaling of its host oncogene.
authors.affiliation: Department of Oncological Sciences, Mitchell Cancer Institute, University of South Alabama, 1600 Springhill Ave, Mobile, AL 36604, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Schmitt
authors.affiliation: Department of Oncological Sciences, Mitchell Cancer Institute, University of South Alabama, 1600 Springhill Ave, Mobile, AL 36604, USA.
authors.forename: L
authors.initials: L
authors.lastname: Madeira da Silva
authors.affiliation: 1] Department of Oncological Sciences, Mitchell Cancer Institute, University of South Alabama, 1600 Springhill Ave, Mobile, AL 36604, USA [2] Department of Medical Laboratory Science, Xiangya School of Medicine, Central South University, Changsha 410013, China [3] Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha 410078, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Oncological Sciences, Mitchell Cancer Institute, University of South Alabama, 1600 Springhill Ave, Mobile, AL 36604, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Oncological Sciences, Mitchell Cancer Institute, University of South Alabama, 1600 Springhill Ave, Mobile, AL 36604, USA.
authors.forename: R
authors.initials: R
authors.lastname: Arora
authors.affiliation: Department of Oncological Sciences, Mitchell Cancer Institute, University of South Alabama, 1600 Springhill Ave, Mobile, AL 36604, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lim
authors.affiliation: Department of Comparative Medicine, University of South Alabama, 307 N. University Blvd, Mobile, AL 36688, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Schuler
authors.affiliation: Department of Oncological Sciences, Mitchell Cancer Institute, University of South Alabama, 1600 Springhill Ave, Mobile, AL 36604, USA.
authors.forename: S
authors.initials: S
authors.lastname: McClellan
authors.affiliation: Department of Oncological Sciences, Mitchell Cancer Institute, University of South Alabama, 1600 Springhill Ave, Mobile, AL 36604, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Andrews
authors.affiliation: Department of Pathology, University of South Alabama, 307 N. University Blvd, Mobile, AL 36688, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Kahn
authors.affiliation: 1] Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha 410078, China [2] Hunan Cancer Hospital and the Affiliated Tumor Hospital of Xiang-Ya School of Medicine, Central South University, Changsha 410013, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Oncological Sciences, Mitchell Cancer Institute, University of South Alabama, 1600 Springhill Ave, Mobile, AL 36604, USA.
authors.forename: E-Y E
authors.initials: EY
authors.lastname: Ahn
authors.affiliation: 1] Department of Oncological Sciences, Mitchell Cancer Institute, University of South Alabama, 1600 Springhill Ave, Mobile, AL 36604, USA [2] Department of Biochemistry and Molecular Biology, University of South Alabama, 307 N. University Blvd, Mobile, AL 36688, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tan
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D007438:Introns; D020935:MAP Kinase Signaling System / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D035683:MicroRNAs; D020929:Mitogen-Activated Protein Kinase Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C000605129:MIRN4728 microRNA, human; C508053:ERBB2 protein, human