title: 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.affiliation: Department of Infectious Disease, Shanghai Public Health Clinical Center Affiliated to Fudan University, Shanghai, People's Republic of China.
authors.forename: Yunzhi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Teng
authors.initials: T
authors.lastname: Ma
authors.forename: Shuping
authors.initials: S
authors.lastname: Yang
authors.forename: Mingying
authors.initials: M
authors.lastname: Xia
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Haijia
authors.initials: H
authors.lastname: An
authors.forename: Yajun
authors.initials: Y
authors.lastname: Yang
authors.forename: Shilin
authors.initials: S
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D057809:HEK293 Cells; D025741:HMGA1a Protein / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D025741:HMGA1a Protein; D035683:MicroRNAs; D051058:Oncogene Protein v-akt; D054648:Protein Phosphatase 2; C525710:MIR222, human; C512974:PPP2R2A protein, human