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

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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.

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Acknowledgments

This work was supported by Eleven Fifth Key Research grant from the Ministry of Science and Technology (No. 2008ZX10001-008), the National Science Foundation of China (30700467), and the Key Project of Chinese National Programs (2008ZX10003-010).

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Authors and Affiliations

  1. Department of Infectious Disease, Shanghai Public Health Clinical Center Affiliated to Fudan University, Shanghai, People’s Republic of China

    Yunzhi Zhang

  2. MOE Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai, 200433, People’s Republic of China

    Teng Ma, Shuping Yang, Mingying Xia, Jing Xu, Haijia An, Yajun Yang & Shilin Li

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  1. Yunzhi Zhang
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Correspondence to Shilin Li.

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Zhang, Y., Ma, T., Yang, S. et al. High-mobility group A1 proteins enhance the expression of the oncogenic miR-222 in lung cancer cells. Mol Cell Biochem 357, 363–371 (2011). https://doi.org/10.1007/s11010-011-0907-1

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  • DOI: https://doi.org/10.1007/s11010-011-0907-1

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