title: MicroRNA 4423 is a primate-specific regulator of airway epithelial cell differentiation and lung carcinogenesis.
abstract: Smoking is a significant risk factor for lung cancer, the leading cause of cancer-related deaths worldwide. Although microRNAs are regulators of many airway gene-expression changes induced by smoking, their role in modulating changes associated with lung cancer in these cells remains unknown. Here, we use next-generation sequencing of small RNAs in the airway to identify microRNA 4423 (miR-4423) as a primate-specific microRNA associated with lung cancer and expressed primarily in mucociliary epithelium. The endogenous expression of miR-4423 increases as bronchial epithelial cells undergo differentiation into mucociliary epithelium in vitro, and its overexpression during this process causes an increase in the number of ciliated cells. Furthermore, expression of miR-4423 is reduced in most lung tumors and in cytologically normal epithelium of the mainstem bronchus of smokers with lung cancer. In addition, ectopic expression of miR-4423 in a subset of lung cancer cell lines reduces their anchorage-independent growth and significantly decreases the size of the tumors formed in a mouse xenograft model. Consistent with these phenotypes, overexpression of miR-4423 induces a differentiated-like pattern of airway epithelium gene expression and reverses the expression of many genes that are altered in lung cancer. Together, our results indicate that miR-4423 is a regulator of airway epithelium differentiation and that the abrogation of its function contributes to lung carcinogenesis.
authors.affiliation: Division of Computational Biomedicine, Genetics and Genomics Program, and Pulmonary Center, Department of Medicine, Boston University, Boston, MA 02118.
authors.forename: Catalina
authors.initials: C
authors.lastname: Perdomo
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Campbell
authors.forename: Joseph
authors.initials: J
authors.lastname: Gerrein
authors.forename: Carmen S
authors.initials: CS
authors.lastname: Tellez
authors.forename: Carly B
authors.initials: CB
authors.lastname: Garrison
authors.forename: Tonya C
authors.initials: TC
authors.lastname: Walser
authors.forename: Eduard
authors.initials: E
authors.lastname: Drizik
authors.forename: Huiqing
authors.initials: H
authors.lastname: Si
authors.forename: Adam C
authors.initials: AC
authors.lastname: Gower
authors.forename: Jessica
authors.initials: J
authors.lastname: Vick
authors.forename: Christina
authors.initials: C
authors.lastname: Anderlind
authors.forename: George R
authors.initials: GR
authors.lastname: Jackson
authors.forename: Courtney
authors.initials: C
authors.lastname: Mankus
authors.forename: Frank
authors.initials: F
authors.lastname: Schembri
authors.forename: Carl
authors.initials: C
authors.lastname: O'Hara
authors.forename: Brigitte N
authors.initials: BN
authors.lastname: Gomperts
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
authors.forename: Patrick
authors.initials: P
authors.lastname: Hayden
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D020545:Respiratory Mucosa / Q000166:cytology* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs
keywords: airway epithelium development; microRNA discovery; next-generation sequencing technology; noncoding RNA; tumor suppressor