A role for LRIG1 in the regulation of malignant glioma aggressiveness
A role for LRIG1 in the regulation of malignant glioma aggressiveness
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LRIG1 在调节恶性胶质瘤侵袭性中的作用
DOI：
10.3892/ijo.2013.1776
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发表时间：
2013-03-01
影响因子：
5.2
通讯作者：
Chen, Xiaoping
中科院分区：
文献类型：
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作者：
Mao, Feng;Wang, Baofeng;Chen, Xiaoping
驱动恶性星形细胞肿瘤发展和侵袭性进展的分子机制仍不清楚。最近，在寻找EGF受体的内源性负调控因子的过程中，LRIG1被克隆并鉴定为一个可能的肿瘤抑制基因，在包括星形细胞肿瘤在内的多种人类肿瘤中经常下调。虽然一些研究表明LRIG1在抑制肿瘤发生中的作用，但其确切的作用和潜在的潜在机制仍然不清楚。因此，我们构建了LRIG1的全长表达载体，并在U251恶性胶质瘤细胞系中过表达。四甲基偶氮唑盐和软琼脂克隆实验显示，外源性LRIG1可抑制体外和皮下移植瘤细胞的增殖。另一方面，LRIG1过表达通过显著改变细胞周期蛋白的表达模式而抑制胶质瘤的生长，导致细胞周期延迟。通过跨膜侵袭和伤口划痕实验和明胶酶谱分析，LRIG1通过抑制MMP2和MMP9的产生来抑制U-251 MG细胞的侵袭和迁移。在配体刺激条件下，LRIG1上调的细胞内p-ERK水平无明显变化，而p-AKT水平受到抑制，表明LRIG1对PI3K/AKT通路有更强的抑制作用。我们的研究结果表明，LRIG1通过抑制细胞增殖、迁移和侵袭来限制胶质瘤的侵袭性。将LRIG1修复到胶质瘤细胞中可能提供一种新的治疗策略。
The molecular mechanisms that drive the development and aggressive progression of malignant astrocytic tumors remain obscure. Recently, in the search for endogenous negative regulators of EGF receptor, LRIG1 was cloned and characterized as a putative tumor suppressor gene often downregulated in various human tumors, including astrocytic tumors. Although several studies have implicated the function of LRIG1 in the inhibition of tumorigenesis, its precise role and potential underlying mechanisms remain obscure. Therefore, we generated a full-length expression vector to overexpress LRIG1 in the U251 malignant glioma cell line. Introduction of exogenous LRIG1 into glioma cells inhibited cell proliferation manifested by MTT and soft agar clone assay in vitro and subcutaneously tumor xenografts. On the other hand, LRIG1 overexpression inhibited glioma growth by significantly changing the expression pattern of cyclins, resulting in delayed cell cycle. Employing transwell invasion and wound scratch assay and gelatin zymography, LRIG1 inhibited U-251 MG Cell invasion and migration by attenuating MMP2 and MMP9 production. Under ligand-stimulated conditions, p-ERK levels did not change, whereas p-AKT levels were inhibited in cells with LRIG1 upregulation, indicating that LRIG1 exerts more inhibiting effects on the PI3K/AKT pathway. Our findings suggest that LRIG1 restricted glioma aggressiveness by inhibiting cell proliferation, migration and invasion. Restoration of LRIG1 to glioma cells could offer a novel therapeutic strategy.