MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 68; no. 19; pp. 8164 - 8172
• Main Authors: PAPAGIANNAKOPOULOS, Thales, SHAPIRO, Alice, KOSIK, Kenneth S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-10-2008
• Subjects: Antineoplastic agents; Apoptosis - genetics; Biological and medical sciences; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Proliferation - drug effects; Gene Regulatory Networks - physiology; Gene Targeting; Genes, Mitochondrial - physiology; Genes, p53 - physiology; Genes, Tumor Suppressor - physiology; Glioblastoma - genetics; Glioblastoma - pathology; HeLa Cells; Humans; Medical sciences; MicroRNAs - antagonists & inhibitors; MicroRNAs - physiology; Models, Biological; Neurology; Pharmacology. Drug treatments; RNA, Small Interfering - pharmacology; Signal Transduction - genetics; Transforming Growth Factor beta - genetics; Tumor Cells, Cultured; Tumors; Tumors of the nervous system. Phacomatoses; Nervous system diseases; RNA interference; Targeting; Glioblastoma; Micro RNA; Malignant tumor; In vitro; Malignant glioma; Gene silencing; Target; Central nervous system disease; Network; Cell; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-08-1305

MicroRNA dysregulation is observed in different types of cancer. MiR-21 up-regulation has been reported for the majority of cancers profiled to date; however, knowledge is limited on the mechanism of action of miR-21, including identification of functionally important targets that contribute to its proproliferative and antiapoptotic actions. In this study, we show for the first time that miR-21 targets multiple important components of the p53, transforming growth factor-beta (TGF-beta), and mitochondrial apoptosis tumor-suppressive pathways. Down-regulation of miR-21 in glioblastoma cells leads to derepression of these pathways, causing repression of growth, increased apoptosis, and cell cycle arrest. These phenotypes are dependent on two of the miR-21 targets validated in this study, HNRPK and TAp63. These findings establish miR-21 as an important oncogene that targets a network of p53, TGF-beta, and mitochondrial apoptosis tumor suppressor genes in glioblastoma cells.