MicroRNA-149 Inhibits Proliferation and Cell Cycle Progression through the Targeting of ZBTB2 in Human Gastric Cancer

• DOI: 10.1371/journal.pone.0041693
• Publication Date: 2012-10-29T22:04:03Z
• Authors: Ying Wang; Xiushan Zheng; Zhiyong Zhang; Jinfeng Zhou; Guohong Zhao; Jianjun Yang; Limin Xia; Rui Wang; Xiqiang Cai; Hao Hu; Cailin Zhu; Yongzhan Nie; Kaichun Wu; Dexin Zhang; Daiming Fan
• Keywords: Science; Blotting, Western; Down-Regulation; Resting Phase, Cell Cycle; Cell Line; 03 medical and health sciences; Stomach Neoplasms; Cell Line, Tumor; Humans; 3' Untranslated Regions; Cell Proliferation; 0303 health sciences; Binding Sites; Base Sequence; Reverse Transcriptase Polymerase Chain Reaction; Q; R; G1 Phase; Cell Cycle Checkpoints; Immunohistochemistry; 3. Good health; Gene Expression Regulation, Neoplastic; Repressor Proteins; MicroRNAs; Mutation; Medicine; Research Article

An increasing body of evidence indicates that miR-149 can both suppress and promote tumor growth depending on the tumor type. However, the role of miR-149 in the progression of gastric cancer (GC) remains unknown. Here we report that miR-149 is a tumor suppressor in human gastric cancer. miR-149 expression is decreased in GC cell lines and clinical specimens in comparison to normal gastric epithelial cell and tissues, respectively. The expression levels of miR-149 also correlate with the differentiation degree of GC cells and tissues. Moreover, ectopic expression of miR-149 in gastric cancer cells inhibits proliferation and cell cycle progression by down-regulating ZBTB2, a potent repressor of the ARF-HDM2-p53-p21 pathway, with a potential binding site for miR-149 in its mRNA's 3'UTR. It is also found that ZBTB2 expression increases in GC cells and tissues compared to normal gastric epithelial cell and tissues, respectively. Silencing of ZBTB2 leads to suppression of cell growth and cell cycle arrest in G0/G1 phase, indicating that ZBTB2 may act as an oncogene in GC. Furthermore, transfection of miR-149 mimics into gastric cancer cells induces down-regulation of ZBTB2 and HDM2, and up-regulation of ARF, p53, and p21 compared to the controls. In summary, our data suggest that miR-149 functions as a tumor suppressor in human gastric cancer by, at least partially through, targeting ZBTB2.