Liggins Institute, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Mol Cancer Ther. 2010 Jun;9(6):1697-708. doi: 10.1158/1535-7163.MCT-09-1077. Epub 2010 Jun 8.
We herein show that Artemin (ARTN), one of the glial cell line-derived neurotrophic factor family of ligands, promotes progression of human non-small cell lung carcinoma (NSCLC). Oncomine data indicate that expression of components of the ARTN signaling pathway (ARTN, GFRA3, and RET) is increased in neoplastic compared with normal lung tissues; increased expression of ARTN in NSCLC also predicted metastasis to lymph nodes and a higher grade in certain NSCLC subtypes. Forced expression of ARTN stimulated survival, anchorage-independent, and three-dimensional Matrigel growth of NSCLC cell lines. ARTN increased BCL2 expression by transcriptional upregulation, and inhibition of BCL2 abrogated the oncogenic properties of ARTN in NSCLC cells. Forced expression of ARTN also enhanced migration and invasion of NSCLC cells. Forced expression of ARTN in H1299 cells additionally resulted in larger xenograft tumors, which were highly proliferative, invasive, and metastatic. Concordantly, either small interfering RNA-mediated depletion or functional inhibition of endogenous ARTN with antibodies reduced oncogenicity and invasiveness of NSCLC cells. ARTN therefore mediates progression of NSCLC and may be a potential therapeutic target for NSCLC.
我们在此表明，胶质细胞系衍生的神经营养因子家族配体之一的 Artemin（ARTN）促进了人类非小细胞肺癌（NSCLC）的进展。Oncomine 数据表明，ARTN 信号通路（ARTN、GFRA3 和 RET）的组成部分在肿瘤组织中比正常肺组织中表达增加；在 NSCLC 中 ARTN 的高表达也预测了淋巴结转移和某些 NSCLC 亚型的更高分级。ARTN 的强制表达刺激了 NSCLC 细胞系的存活、锚定独立和三维 Matrigel 生长。ARTN 通过转录上调增加了 BCL2 的表达，而 BCL2 的抑制消除了 ARTN 在 NSCLC 细胞中的致癌特性。ARTN 的强制表达还增强了 NSCLC 细胞的迁移和侵袭。在 H1299 细胞中强制表达 ARTN 还导致更大的异种移植物肿瘤，这些肿瘤具有高度增殖性、侵袭性和转移性。一致地，通过 siRNA 介导的耗尽或使用抗体对内源性 ARTN 的功能抑制减少了 NSCLC 细胞的致癌性和侵袭性。因此，ARTN 介导了 NSCLC 的进展，可能是 NSCLC 的潜在治疗靶点。
