title: MiR-99a regulates ROS-mediated invasion and migration of lung adenocarcinoma cells by targeting NOX4.
abstract: miR-99a is frequently downregulated in various types of human malignancies including lung adenocarcinoma. Recent studies have reported that miR-99a regulates cell growth and cell cycle progression by targeting mTOR, AKT1 and FGFR3. However, the underlying mechanisms involved in the modulation of invasion and migration by miR-99a remain elusive. In this study, we analyzed the relationship between the expression of miR-99a and clinical stage or metastasis in 90 matched lung adenocarcinoma and adjacent non-tumor lung tissues. Downregulation of miR-99a was significantly associated with advanced stage and tumor metastasis in lung adenocarcinoma patients, and it was found to be a poor prognostic factor in lung adenocarcinoma. Furthermore, functional experiments found that overexpression of miR-99a inhibited the proliferation, migration and invasion of lung adenocarcinoma A549 and Calu3 cells in vitro. We then identified NOX4 as a target gene of miR-99a and NOX4 mediated the inhibition of invasion and migration of lung adenocarcinoma cells by miR-99a. By targeting NOX4-mediated ROS production, miR-99a regulated the invasion and migration of lung adenocarcinoma cells. Moreover, overexpression of miR-99a significantly inhibited tumor growth in vivo. Immunohistochemical staining analysis of the mouse tumor tissues revealed that NOX4 levels were downregulated in the miR-99a treatment group, confirming the in vitro data of NOX4 as a direct target gene of miR-99a. Taken together, these data indicate for the first time that miR-99a directly regulates the invasion and migration in lung adenocarcinoma by targeting NOX4 and that overexpression of miR-99a may become a therapeutic strategy for lung adenocarcinoma.
authors.affiliation: Department of Radiation Oncology, Tianjin Huan Hu Hospital, Tianjin 300060, P.R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Postgraduate Studies, Tianjin Medical University, Tianjin 300070, P.R. China.
authors.forename: Shunming
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Postgraduate Studies, Tianjin Medical University, Tianjin 300070, P.R. China.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Postgraduate Studies, Tianjin Medical University, Tianjin 300070, P.R. China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China.
authors.forename: Jinqiang
authors.initials: J
authors.lastname: You
authors.affiliation: Department of Pathology, Tianjin Huan Hu Hospital, Tianjin 300060, P.R. China.
authors.forename: Xuebin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Tianjin Huan Hu Hospital, Tianjin 300060, P.R. China.
authors.forename: Fan
authors.initials: F
authors.lastname: Tang
authors.affiliation: Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Tianjin Huan Hu Hospital, Tianjin 300060, P.R. China.
authors.forename: Chunzhi
authors.initials: C
authors.lastname: Zhang
mesh_terms: D020413:3' Untranslated Regions; D000072283:A549 Cells; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002465:Cell Movement; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C561679:MIRN99 microRNA, human; D035683:MicroRNAs; D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human