title: FHIT suppresses epithelial-mesenchymal transition (EMT) and metastasis in lung cancer through modulation of microRNAs.
abstract: Metastasis is the principal cause of cancer death and occurs through multiple, complex processes that involve the concerted action of many genes. A number of studies have indicated that the Fragile Histidine Triad (FHIT) gene product, FHIT, functions as a tumor suppressor in a variety of common human cancers. Although there are suggestions of a role for FHIT loss in progression of various cancers, a role for such loss in metastasis has not been defined. Here, via in vivo and in vitro assays, we reveal that the enforced expression of FHIT significantly suppresses metastasis, accompanied by inhibition of the epithelial-mesenchymal transition (EMT), a process involved in metastasis through coordinate modulation of EMT-related genes. Specifically, miR-30c, a FHIT-upregulated microRNA, contributes to FHIT function in suppression of EMT and metastasis by directly targeting metastasis genes Metadherin (MTDH), High-mobility group AT-hook 2 (HMGA2), and the mesenchymal markers, Vimentin (VIM) and Fibronectin (FN1), in human lung cancer. Finally, we demonstrate that the expression pattern of FHIT and miR-30c is inversely correlated with that of MTDH and HMGA2 in normal tissue, non-metastatic and metastatic tumors, serving as a potential biomarker for metastasis in lung cancer.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America; South Sea Environmental Research Division, Korea Institute of Ocean Science and Technology, Geoje, South Korea.
authors.forename: Sung-Suk
authors.initials: SS
authors.lastname: Suh
authors.affiliation: Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, Comprehensive Cancer Center and The Ohio State University Medical Center, Columbus, Ohio, United States of America.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Ri
authors.initials: R
authors.lastname: Cui
authors.affiliation: Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, Comprehensive Cancer Center and The Ohio State University Medical Center, Columbus, Ohio, United States of America.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
authors.affiliation: South Sea Environmental Research Division, Korea Institute of Ocean Science and Technology, Geoje, South Korea.
authors.forename: Taek-Kyun
authors.initials: TK
authors.lastname: Lee
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America; The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000096:biosynthesis / Q000235:genetics*; D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005353:Fibronectins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000096:biosynthesis; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D016601:RNA-Binding Proteins; D014746:Vimentin / Q000096:biosynthesis; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D025743:HMGA2 Protein; D008565:Membrane Proteins; D035683:MicroRNAs; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D014746:Vimentin; D000099170:Bis(5'-adenosyl)triphosphatase; C546086:MIRN30b microRNA, human; C483039:MTDH protein, human