title: Overexpression of microRNA-95-3p suppresses brain metastasis of lung adenocarcinoma through downregulation of cyclin D1.
abstract: Despite great efforts to improve survival rates, the prognosis of lung cancer patients is still very poor, mainly due to high invasiveness. We developed brain metastatic PC14PE6/LvBr4 cells through intracardiac injection of lung adenocarcinoma PC14PE6 cells. Western blot and RT-qPCR analyses revealed that PC14PE6/LvBr4 cells had mesenchymal characteristics and higher invasiveness than PC14PE6 cells. We found that cyclin D1 was upregulated, miR-95-3p was inversely downregulated, and pri-miR-95 and its host gene, ABLIM2, were consistently decreased in PC14PE6/LvBr4 cells. MiR-95-3p suppressed cyclin D1 expression through direct binding to the 3' UTR of cyclin D1 mRNA and suppressed invasiveness, proliferation, and clonogenicity of PC14PE6/LvBr4 cells. Ectopic cyclin D1 reversed miR-95-3p-mediated inhibition of invasiveness and clonogenicity, demonstrating cyclin D1 downregulation is involved in function of miR-95-3p. Using bioluminescence imaging, we found that miR-95-3p suppressed orthotopic tumorigenicity and brain metastasis in vivo and increased overall survival and brain metastasis-free survival. Consistent with in vitro metastatic cells, the levels of miR-95-3p, pri-miR-95, and ABLIM2 mRNA were decreased in brain metastatic tissues compared with lung cancer tissues and higher cyclin D1 expression was involved in poor prognosis. Taken together, our results demonstrate that miR-95-3p is a potential therapeutic target for brain metastasis of lung adenocarcinoma cells.
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Hye Ree
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Song
authors.affiliation: Department of Neurosurgery, Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Dong Heon
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Hong
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Shin
authors.affiliation: Translational Bioinformatics Laboratory, Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Je-Gun
authors.initials: JG
authors.lastname: Joung
authors.affiliation: Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.|Center for Genome Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Duk-Hwan
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.|Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.|Samsung Biomedical Research Institute, Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.
authors.forename: Hyeon Ho
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009362:Neoplasm Metastasis; D011379:Prognosis; D014162:Transfection
chemical_list: C530104:CCND1 protein, human; C575854:MIRN95 microRNA, human; D035683:MicroRNAs; D019938:Cyclin D1
keywords: brain metastasis; cyclin D1; lung adenocarcinoma; microRNA-95-3p