MicroRNA-302a Suppresses Tumor Cell Proliferation by Inhibiting AKT in Prostate Cancer

Gui-Ming Zhang; Chun-Yang Bao; Fang-Ning Wan; Da-Long Cao; Xiao-Jian Qin; Hai-Liang Zhang; Yao Zhu; Bo Dai; Guo-Hai Shi; Ding-Wei Ye

doi:10.1371/journal.pone.0124410

MicroRNA-302a Suppresses Tumor Cell Proliferation by Inhibiting AKT in Prostate Cancer

PLoS One. 2015 Apr 29;10(4):e0124410. doi: 10.1371/journal.pone.0124410. eCollection 2015.

Authors

Affiliations

¹ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
² State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Abstract

Micro (mi) RNAs are important regulators involved in various physical and pathological processes, including cancer. The miRNA-302 family has been documented as playing a critical role in carcinogenesis. In this study, we investigated the role of miRNA-302a in prostate cancer (PCa). MiRNA-302a expression was detected in 44 PCa tissues and 10 normal prostate tissues, and their clinicopathological significance was analyzed. Cell proliferation and cell cycle analysis were performed on PCa cells that stably expressed miRNA-302a. The target gene of miRNA-302a and the downstream pathway were further investigated. Compared with normal prostate tissues, miRNA-302a expression was downregulated in PCa tissues, and was even lower in PCa tissues with a Gleason score ≥8. Overexpression of miRNA-302a induced G1/S cell cycle arrest in PCa cells, and suppressed PCa cell proliferation both in vitro and in vivo. Furthermore, miRNA-302a inhibits AKT expression by directly binding to its 3΄ untranslated region, resulting in subsequent alterations of the AKT-GSK3β-cyclin D1 and AKT-p27Kip1 pathway. These results reveal miRNA-302a as a tumor suppressor in PCa, suggesting that miRNA-302a may be used as a potential target for therapeutic intervention in PCa.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Cell Line, Tumor
Cell Proliferation
Cyclin D1 / genetics
Cyclin D1 / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / genetics
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
G1 Phase Cell Cycle Checkpoints / genetics
Gene Expression Regulation, Neoplastic*
Genetic Vectors / administration & dosage*
Genetic Vectors / metabolism
Glycogen Synthase Kinase 3 / genetics
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
HEK293 Cells
Humans
Lentivirus / genetics
Male
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / genetics*
MicroRNAs / metabolism
Neoplasm Grading
Neoplasm Transplantation
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Prostatic Neoplasms / therapy*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction

Substances

CCND1 protein, human
CDKN1B protein, human
MIRN302A microRNA, human
MicroRNAs
Cyclin D1
Cyclin-Dependent Kinase Inhibitor p27
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Proto-Oncogene Proteins c-akt
Glycogen Synthase Kinase 3

Grants and funding

This study was supported by grants from National Natural Science Foundation of China (Grant No. NSFC 81202003) (http://www.nsfc.gov.cn/) and Science Foundation of Shanghai Municipal Commission of Health and Family Planning (Grant No. 2010145) (http://www.wsjsw.gov.cn/wsj/) to GHS.