Characterization and Evidence of the miR-888 Cluster as a Novel Cancer Network in Prostate
Abstract
Prostate cancer afflicts 1 in 7 men and is the second leading cause of male cancer-related deaths in the United States. MicroRNAs (miRNAs), an extensive class of approximately 22 nucleotide noncoding RNAs, are often aberrantly expressed in tissues and fluids from prostate cancer patients, but the mechanisms of how specific miRNAs regulate prostate tumorigenesis and metastasis are poorly understood. Here, miR-888 was identified as a novel prostate factor that promotes proliferation and migration. miR-888 resides within a genomic cluster of 7 miRNA genes (mir-892c, mir-890, mir-888, mir-892a, mir-892b, mir-891b, mir-891a) on human chromosome Xq27.3. Moreover, as miR-888 maps within HPCX1, a locus associated with susceptibility and/or hereditary prostate cancer, it was hypothesized that additional miRNA cluster members also play functional roles in the prostate. Expression analysis determined that cluster members were similarly elevated in metastatic PC3-ML prostate cells and their secreted exosomes, as well as enriched in expressed prostatic secretions urine-derived exosomes obtained from clinical patients with high-grade prostate cancer. In vitro assays revealed that miR-888 cluster members selectively modulated PC3-derived and LNCaP cell proliferation, migration, invasion, and colony formation. Mouse xenograft studies verified miR-888 and miR-891a as pro-oncogenic factors that increased prostate tumor growth in vivo. Further analysis validated RBL1, KLF5, SMAD4, and TIMP2 as direct miR-888 targets and that TIMP2 is also coregulated by miR-891a. This study provides the first comprehensive analysis of the entire miR-888 cluster and reveals biological insight.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2018
- Source ID
- 10.1158/1541-7786.mcr-17-0321
Entities
People
- Aleena Short
- Aurora Esquela-kerscher
- Garrison J. Glavich
- Lifang Yang
- Mary Pahuski
- O. John Semmes
- Richard Drake
- Tsuyoshi Hasegawa
- Vitold Galkin
Organizations
- Eastern Virginia Medical School
- Medical University of South Carolina
- National Cancer Institute
- United States Department of Defense