Tan Li, Wei Xiaoping, Zheng Lixia, Zeng Jincai, Liu Haibo, Yang Shaojiang, Tan Huo
Center of Oncology and Hematology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510230, China.
Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou, 510230, China.
J Cancer Res Clin Oncol. 2016 Feb;142(2):389-99. doi: 10.1007/s00432-015-2036-9. Epub 2015 Aug 30.
The aim of this study was to investigate how the amplification of HMGA2 contributes to acute myeloid leukemia (AML) cell proliferation.
The amplification and expression of HMGA2 were examined by FISH, qRT-PCR and Western blot in AML cases. The effect of HMGA2 knockdown on cell proliferation was analyzed with XTT, colony-forming assays and BrdUrd incorporation assays. The effects of HMGA2 knockdown on cell cycle were studied by flow cytometry analysis. The progression of AML cells in vivo was examined by the xenografted tumor model. The interaction between Akt pathway and HMGA2 was examined by Western blot.
HMGA2 is amplified in AML, and the levels of HMGA2 messenger RNA (mRNA) and protein expressed in AML cells were significantly higher than those in normal cells, which may be related to NR and prognosis of AML patients. Reduction in HMGA2 expression in AML cells inhibited cell proliferation through a decrease in the protein expression of pAkt and pmTOR, compared with control cells.
HMGA2 is predominantly amplified and expressed in AML cells, and that aberrant expression of HMGA2 induces AML cell proliferation through the PI3K/Akt/mTOR signaling pathway. Inhibition of HMGA2 expression represents an attractive target for AML therapy.
本研究旨在探究HMGA2的扩增如何促进急性髓系白血病（AML）细胞增殖。
采用荧光原位杂交（FISH）、定量逆转录聚合酶链反应（qRT-PCR）和蛋白质免疫印迹法检测AML病例中HMGA2的扩增及表达情况。通过XTT法、集落形成试验和5-溴脱氧尿嘧啶核苷（BrdUrd）掺入试验分析敲低HMGA2对细胞增殖的影响。通过流式细胞术分析研究敲低HMGA2对细胞周期的影响。利用异种移植肿瘤模型检测AML细胞在体内的进展情况。通过蛋白质免疫印迹法检测Akt信号通路与HMGA2之间的相互作用。
HMGA2在AML中呈扩增状态，AML细胞中HMGA2信使核糖核酸（mRNA）和蛋白水平显著高于正常细胞，这可能与AML患者的核仁组成区（NR）及预后相关。与对照细胞相比，AML细胞中HMGA2表达降低通过降低磷酸化Akt（pAkt）和磷酸化哺乳动物雷帕霉素靶蛋白（pmTOR）的蛋白表达来抑制细胞增殖。
HMGA2在AML细胞中主要呈扩增及高表达状态，且HMGA2的异常表达通过磷脂酰肌醇-3激酶（PI3K）/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路诱导AML细胞增殖。抑制HMGA2表达是AML治疗的一个有吸引力的靶点。
