Kouhkan Fatemeh, Mobarra Naser, Soufi-Zomorrod Mina, Keramati Farid, Hosseini Rad Seyed Mohammad Ali, Fathi-Roudsari Mehrnoosh, Tavakoli Rezvan, Hajarizadeh Athena, Ziaei Said, Lahmi Reyhaneh, Hanif Hamed, Soleimani Masoud
Department of Molecular Biology and Genetic Engineering, Stem Cell Technology Research Center, Tehran, Iran.
Metabolic Disorders Research Center, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
J Med Genet. 2016 Jan;53(1):24-33. doi: 10.1136/jmedgenet-2015-103225. Epub 2015 Oct 28.
MicroRNA-129-1 (miR-129-1) seems to behave as a tumour suppressor since its decreased expression is associated with different tumours such as glioblastoma multiforme (GBM). GBM is the most common form of brain tumours originating from glial cells. The impact of miR-129-1 downregulation on GBM pathogenesis has yet to be elucidated.
MiR-129-1 was overexpressed in GBM cells, and its effect on proliferation was investigated by cell cycle assay. MiR-129-1 predicted targets (CDK6, IGF1, HDAC2, IGF2BP3 and MAPK1) were also evaluated by western blot and luciferase assay.
Restoration of miR-129-1 reduced cell proliferation and induced G1 accumulation, significantly. Several functional assays confirmed IGF2BP3, MAPK1 and CDK6 as targets of miR-129-1. Despite the fact that IGF1 expression can be suppressed by miR-129-1, through 3'-untranslated region complementary sequence, we could not find any association between IGF1 expression and GBM. MiR-129-1 expression inversely correlates with CDK6, IGF2BP3 and MAPK1 in primary clinical samples.
This is the first study to propose miR129-1 as a negative regulator of IGF2BP3 and MAPK1 and also a cell cycle arrest inducer in GBM cells. Our data suggests miR-129-1 as a potential tumour suppressor and presents a rationale for the use of miR-129-1 as a novel strategy to improve treatment response in GBM.
微小RNA - 129 - 1（miR - 129 - 1）似乎起着肿瘤抑制因子的作用，因为其表达降低与多种肿瘤相关，如多形性胶质母细胞瘤（GBM）。GBM是源自神经胶质细胞的最常见的脑肿瘤形式。miR - 129 - 1下调对GBM发病机制的影响尚待阐明。
在GBM细胞中过表达miR - 129 - 1，并通过细胞周期分析研究其对增殖的影响。还通过蛋白质印迹和荧光素酶测定评估miR - 129 - 1预测的靶标（细胞周期蛋白依赖性激酶6（CDK6）、胰岛素样生长因子1（IGF1）、组蛋白去乙酰化酶2（HDAC2）、胰岛素样生长因子2结合蛋白3（IGF2BP3）和丝裂原活化蛋白激酶1（MAPK1））。
miR - 129 - 1的恢复显著降低了细胞增殖并诱导了G1期积累。多项功能测定证实IGF2BP3、MAPK1和CDK6是miR - 129 - 1的靶标。尽管miR - 129 - 1可通过3' - 非翻译区互补序列抑制IGF1表达，但我们未发现IGF1表达与GBM之间存在任何关联。在原发性临床样本中，miR - 129 - 1表达与CDK6、IGF2BP3和MAPK1呈负相关。
这是第一项提出miR129 - 1作为IGF2BP3和MAPK1的负调节因子以及GBM细胞中细胞周期阻滞诱导剂的研究。我们的数据表明miR - 129 - 1是一种潜在的肿瘤抑制因子，并为将miR - 129 - 1用作改善GBM治疗反应的新策略提供了理论依据。
