Tumor-suppressive effect of LRIG1, a negative regulator of ErbB, in non-small cell lung cancer harboring mutant EGFR
Tumor-suppressive effect of LRIG1, a negative regulator of ErbB, in non-small cell lung cancer harboring mutant EGFR
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DOI：
10.1093/carcin/bgy044
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发表时间：
2018-05-01
期刊：
影响因子：
4.7
通讯作者：
Toyooka, Shinichi
中科院分区：
文献类型：
--
作者：
Torigoe, Hidejiro;Yamamoto, Hiromasa;Toyooka, Shinichi
表皮生长因子受体(EGFR)是ErbB(HER)家族的成员，在多种人类癌症的发病机制中发挥重要作用。EGFR基因突变通常被发现为致癌基因突变，并已被靶向治疗非小细胞肺癌(NSCLC)。亮氨酸重复序列和免疫球蛋白样域蛋白-1(LRIG1)是一种细胞表面蛋白，被认为是ErbB(HER)家族的负调控因子。在本研究中，我们首先证实了LRIG1在非小细胞肺癌组织中的表达水平明显低于非恶性细胞或组织。接下来，我们重点研究LRIG1在非小细胞肺癌中的作用。为此，我们使用EGFR突变体(HCC827、HCC4011和NCI-H1975)和野生型(A549)细胞建立了稳定高表达LRIG1的克隆。LRIG1基因的表达与HCC827、HCC4011和NCI-H1975细胞中EGFR的表达和磷酸化水平降低有关。它还与对HCC827细胞的细胞增殖、侵袭、迁移和致瘤能力的强烈抑制有关。另一方面，在A549细胞中没有观察到这种作用。此外，LRIG1还下调了HER2、HER3、MET和IGF-1R等其他酪氨酸激酶受体的表达和磷酸化水平，并阻止了转化生长因子-β诱导的HCC827细胞上皮向间充质转化。这些发现表明，LRIG1在EGFR突变的NSCLC中具有重要的肿瘤抑制作用，有可能成为EGFR突变的NSCLC的新的治疗靶点。
Epidermal growth factor receptor (EGFR) is a member of the ErbB (HER) family that is known to play important roles in the pathogenesis of various human cancers. Mutations of the EGFR gene are commonly found as oncogenic driver mutations and have been targeted for treatment of non-small cell lung cancer (NSCLC). Leucine-rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell-surface protein that is known as a negative regulator of the ErbB (HER) family. In this study, we first confirmed that the expression levels of LRIG1 were much lower in NSCLC than in non-malignant cells or tissues. Next, we focused on the effect of LRIG1 in NSCLC. For this purpose, we established clones stably overexpressing LRIG1, using EGFR-mutant (HCC827, HCC4011 and NCI-H1975) and wild-type (A549) cells. Transfection of LRIG1 was associated with a decrease in the expression and phosphorylation levels of EGFR in the HCC827, HCC4011 and NCI-H1975 cells. It was also associated with strong suppression of the cell proliferative, invasive, migratory and tumorigenic potential of the HCC827 cells. On the other hand, no such effects were observed in the A549 cells. In addition, LRIG1 also downregulated the expression and phosphorylation levels of other tyrosine kinase receptors, such as HER2, HER3, MET and IGF-1R, and prevented the epithelial-to-mesenchymal transition induced by TGF-beta in the HCC827 cells. These findings suggest that LRIG1 exerts important tumor-suppressive effects in EGFR-mutant NSCLC and has the potential to become a novel therapeutic target for EGFR-mutant NSCLC.