Ye Fei, Gao Qinglei, Xu Tongjiang, Zeng Liang, Ou Yibo, Mao Feng, Wang Heping, He Yue, Wang Baofeng, Yang Zhengming, Guo Dongsheng, Lei Ting
Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jie-Fang Avenue, Wuhan, Hubei, 430030, People's Republic of China.
J Neurooncol. 2009 Sep;94(2):183-94. doi: 10.1007/s11060-009-9836-1. Epub 2009 Mar 20.
Activated epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target for a variety of solid tumors, particularly malignant gliomas. A recently discovered transmembrane glycoprotein, LRIG1, antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases and acts as a negative feedback loop of EGFR and proposed tumor suppressors. The aim of this study was to investigate the impact of LRIG1 on the biological features of glioma cells and the possible mechanisms of enhanced apoptosis induced by upregulation of LRIG1. We observed that the expression of LRIG1 was decreased, while the expression of EGFR was increased in the majority of astrocytomas, and the ratio of EGFR/LRIG1 was increased by sixfold in tumors versus corresponding non-neoplastic tissue. Upregulation of LRIG1, followed by a decrease of EGFR on the cytomembrane of the cells, induced cell apoptosis and cell growth inhibition, and further reversed invasion in glioma cell lines and primary glioma cells. Our study now clearly indicates that LRIG1 indeed affects cell fate and biology behaviors of the cells in vitro by inhibiting phosphorylation of downstream MAPK and AKT signaling pathway, and the elevated release level of caspase-8 might contribute to the enhanced apoptosis in LRIG1 transfected glioma cells. Taken together, these findings provide us with an insight into LRIG1 function, and we conclude that LRIG1 evolved in gliomas as a rare feedback negative attenuator of EGFR and could offer a novel therapeutic target to treat patients with malignant gliomas.
活化的表皮生长因子受体（EGFR）已成为多种实体瘤尤其是恶性胶质瘤的重要治疗靶点。最近发现的一种跨膜糖蛋白LRIG1可拮抗表皮生长因子受体家族受体酪氨酸激酶的活性，并作为EGFR的负反馈环和潜在的肿瘤抑制因子。本研究的目的是探讨LRIG1对胶质瘤细胞生物学特性的影响以及LRIG1上调诱导细胞凋亡增强的可能机制。我们观察到，在大多数星形细胞瘤中，LRIG1的表达降低，而EGFR的表达增加，肿瘤组织中EGFR/LRIG1的比值相对于相应的非肿瘤组织增加了6倍。LRIG1上调后，细胞细胞膜上的EGFR减少，诱导细胞凋亡和细胞生长抑制，并进一步逆转胶质瘤细胞系和原代胶质瘤细胞的侵袭能力。我们的研究现在清楚地表明，LRIG1确实通过抑制下游MAPK和AKT信号通路的磷酸化在体外影响细胞命运和生物学行为，并且caspase-8释放水平的升高可能有助于LRIG1转染的胶质瘤细胞凋亡增强。综上所述，这些发现为我们深入了解LRIG1的功能提供了依据，我们得出结论，LRIG1在胶质瘤中作为EGFR罕见的反馈负性衰减因子发挥作用，并可为治疗恶性胶质瘤患者提供新的治疗靶点。
