miR-99a regulates ROS-mediated invasion and migration of lung adenocarcinoma cells by targeting NOX4

Sun,Mei; Hong,Shunming; Li,Wenhan; Wang,Pengfei; You,Jinqiang; Zhang,Xuebin; Tang,Fan; Wang,Ping; Zhang,Chunzhi

doi:10.3892/or.2016.4672

miR-99a regulates ROS-mediated invasion and migration of lung adenocarcinoma cells by targeting NOX4

Authors:
- Mei Sun
- Shunming Hong
- Wenhan Li
- Pengfei Wang
- Jinqiang You
- Xuebin Zhang
- Fan Tang
- Ping Wang
- Chunzhi Zhang
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Affiliations: Department of Radiation Oncology, Tianjin Huan Hu Hospital, Tianjin 300060, P.R. China, Department of Postgraduate Studies, Tianjin Medical University, Tianjin 300070, P.R. China, 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, Department of Pathology, Tianjin Huan Hu Hospital, Tianjin 300060, P.R. China
Published online on: March 11, 2016 https://doi.org/10.3892/or.2016.4672
Pages: 2755-2766

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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.

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