title: MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer.
abstract: Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identify microRNA-224 (miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. Increased miR-224 expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNFα-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated that miR-224 functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation of miR-224 expression in NSCLC. Up-regulated miR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targeting miR-224 could be effective in the treatment of certain lung cancer patients.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Chemical Biology Research Center, School of Pharmaceutical Sciences and Lung Cancer Research Center, Zhoushan Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China;
authors.forename: Ri
authors.initials: R
authors.lastname: Cui
authors.affiliation: Department of Radiation Oncology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Wei
authors.initials: W
authors.lastname: Meng
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Hui-Lung
authors.initials: HL
authors.lastname: Sun
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Taewan
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine/Institute of Biotechnology, South Texas Research Facility, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900;
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Applied Research on Cancer Network (ARC-NET) Research Centre, University of Verona, Verona 37126, Italy;
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Department of Radiation Oncology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Applied Research on Cancer Network (ARC-NET) Research Centre, University of Verona, Verona 37126, Italy;
authors.forename: Caterina
authors.initials: C
authors.lastname: Vicentini
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Yong
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Lee
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Department of Pathology, Affiliated Hospital of YanBian University, Ji Lin 133002, China;
authors.forename: Lan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pathology, Affiliated Hospital of YanBian University, Ji Lin 133002, China;
authors.forename: Dongyuan
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Department of Anesthesiology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.
authors.forename: Esmerina
authors.initials: E
authors.lastname: Tili
authors.affiliation: Department of Molecular Medicine/Institute of Biotechnology, South Texas Research Facility, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900;
authors.forename: Victor
authors.initials: V
authors.lastname: Jin
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Justin
authors.initials: J
authors.lastname: Middleton
authors.affiliation: Department of Radiation Oncology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: Department of Radiation Oncology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; TimLautenschlaeger01@gmail.com carlo.croce@osumc.edu.
authors.forename: Tim
authors.initials: T
authors.lastname: Lautenschlaeger
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; TimLautenschlaeger01@gmail.com carlo.croce@osumc.edu.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008207:Lymphatic Metastasis; D020935:MAP Kinase Signaling System / Q000235:genetics; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; C546140:MIRN224 microRNA, human; D035683:MicroRNAs; D011506:Proteins; D051901:Smad4 Protein; C115968:TNFAIP1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: NSCLC; SMAD4; TNFAIP1; metastasis; microRNA