Upregulation of MircoRNA-370 induces proliferation in human prostate cancer cells by downregulating the transcription factor FOXO1

• Published in: PloS one 2012-09, Vol.7 (9), p.e45825-e45825
• Main Authors: Wu, Ziqing, Sun, Huabin, Zeng, Weixia, He, Jincan, Mao, Xiangming
• Format: Article
• Language: English
• Subjects: Androgens; Angiogenesis; Apoptosis; Base Sequence; Biology; Cancer; Cancer therapies; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation; Colonies; Cyclin D1; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-dependent kinase inhibitor p27; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Development and progression; Down-Regulation; Ectopic expression; Forkhead Box Protein O1; Forkhead protein; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXO1 protein; G1 Phase Cell Cycle Checkpoints; Gene Expression; Gene Expression Regulation, Neoplastic; Gene silencing; Genetic aspects; Humans; Kinases; Male; Medicine; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Physiological aspects; Prostate cancer; Prostatic Neoplasms; Transcription factors; Tumor cell lines; Tumor suppressor genes; Up-Regulation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0045825

Forkhead box protein O1 (FOXO1), a key member of the FOXO family of transcription factors, acts as a tumor suppressor and has been associated with various key cellular functions, including cell growth, differentiation, apoptosis and angiogenesis. Therefore, it is puzzling why FOXO protein expression is downregulated in cancer cells. MicroRNAs, non-coding 20~22 nucleotide single-stranded RNAs, result in translational repression or degradation and gene silencing of their target genes, and significantly contribute to the regulation of gene expression. In the current study, we report that miR-370 expression was significantly upregulated in five prostate cancer cell lines, compared to normal prostatic epithelial (PrEC) cells. Ectopic expression of miR-370 induced proliferation and increased the anchorage-independent growth and colony formation ability of DU145 and LNCaP prostate cancer cells, while inhibition of miR-370 reduced proliferation, anchorage-independent growth and colony formation ability. Furthermore, upregulation of miR-370 promoted the entry of DU145 and LNCaP prostate cancer cells into the G1/S cell cycle transition, which was associated with downregulation of the cyclin-dependent kinase (CDK) inhibitors, p27(Kip1) and p21(Cip1), and upregulation of the cell-cycle regulator cyclin D1 mRNA. Additionally, we demonstrated that miR-370 can downregulate expression of FOXO1 by directly targeting the FOXO1 3'-untranslated region. Taken together, our results suggest that miR-370 plays an important role in the proliferation of human prostate cancer cells, by directly suppressing the tumor suppressor FOXO1.