Abstract
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.
Highlights
Lung carcinoma is currently responsible for the highest cancer-related mortality worldwide, with overall 5-year survival approximating 15% [1, 2]
To determine the expression of components of the ARTN signaling pathway in non–small cell lung carcinoma (NSCLC), the mRNA expression of ARTN, GFRA1-A3, and RET was determined by semiquantitative reverse transcription-PCR (RT-PCR) in a panel of five human NSCLC cell lines: H1299, H1975, H460, H2009, and A549
ARTN expression was significantly increased in carcinoid, NSCLC, and small cell carcinoma compared with normal lung (Supplementary Table S1a)
Summary
Lung carcinoma is currently responsible for the highest cancer-related mortality worldwide, with overall 5-year survival approximating 15% [1, 2]. Early diagnosis of lung carcinoma remains challenging, the lack of effective approaches to prevent disease progression persists. As a result of advances in cancer biology during the last few decades, a number of targeted agents have been developed, exemplified by erlotinib/gefitinib, which selectively inhibits the epidermal growth factor receptor [3]. Clinical application of these agents has provided only limited therapeutic benefits for patients with lung carcinoma [4,5,6], partially attributable to the compensatory effect of other cellular mechanisms exploited by the tumors for survival and progression [3].
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