Overexpression of microRNA-95-3p suppresses brain metastasis of lung adenocarcinoma through downregulation of cyclin D1
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Su Jin Hwang1,*, Hye Won Lee2,*, Hye Ree Kim1, Hye Jin Song4, Dong Heon Lee3, Hong Lee1, Chang Hoon Shin1, Je-Gun Joung5, Duk-Hwan Kim4,6, Kyeung Min Joo1,4, Hyeon Ho Kim1,7
1Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea
2Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
3Department of Neurosurgery, Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
4Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea
5Translational Bioinformatics Laboratory, Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
6Center for Genome Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
7Samsung Biomedical Research Institute, Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
*These authors have contributed equally to this work
Hyeon Ho Kim, e-mail: [email protected]
Kyeung Min Joo, e-mail: [email protected]
Keywords: microRNA-95-3p, brain metastasis, cyclin D1, lung adenocarcinoma
Received: January 18, 2015 Accepted: April 25, 2015 Published: May 07, 2015
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.
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