High-mobility group A1 proteins enhance the expression of the oncogenic miR-222 in lung cancer cells.

Abstract

High-mobility group A1 (HMGA1) is a non-histone chromatin protein that has the ability to regulate the transcriptional activity of many genes. Overexpression of HMGA1 is associated with malignant cellular behavior in a range of human cancers but the underlying mechanism is largely unknown. Here we showed that in a cohort of non-small cell lung cancer (NSCLC) tumors, HMGA1 overexpression was immediately associated with enhanced expression of an oncogenic miRNA, namely, miR-222. Chromatin immunoprecipitation (CHIP) assay revealed that HMGA1 directly binds to the proximal promoter of miR-222 in NSCLC cells. We further showed that HMGA1 silencing reduced miR-222 transcriptional activity, whereas forced HMGA1 expression increased it, indicating that miR-222 is directly regulated by HMGA1. Based on in silico prediction, one of the putative targets of miR-222 is phosphatase 2A subunit B (PPP2R2A) which inhibits Akt phosphorylation (p-Akt). We demonstrated that miR-222 inhibited protein expression of PPP2R2A in NSCLC cells by directly interacting with its 3'-UTR region, leading to an obvious increase of p-Akt. HMGA1 silencing augmented PPP2R2A protein expression and inhibited Akt signaling, resulting in significantly retarded cell growth response to IGF-I. These results suggested that HMGA1 is a positive regulator of miR-222, and HMGA1 overexpression might contribute to dysregulation of Akt signaling in NSCLC.

• Authors: Yunzhi Zhang, Teng Ma, Shuping Yang, Mingying Xia, Jing Xu, Haijia An, Yajun Yang, Shilin Li
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 357 Issue 1-2 Pg. 363-71 (Nov 2011) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 21656127 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• MIRN222 microRNA, human
• MicroRNAs
• PPP2R2A protein, human
• HMGA1a Protein
• Oncogene Protein v-akt
• Protein Phosphatase 2

Topics

• 3' Untranslated Regions
• Base Sequence
• Binding Sites
• Carcinoma, Non-Small-Cell Lung (metabolism, pathology)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• HEK293 Cells
• HMGA1a Protein (genetics, metabolism)
• Humans
• Lung Neoplasms (metabolism, pathology)
• MicroRNAs (genetics, metabolism)
• Molecular Sequence Data
• Oncogene Protein v-akt (metabolism)
• Phosphorylation
• Protein Binding
• Protein Phosphatase 2 (metabolism)
• Transcriptional Activation (genetics)