Artemin-Stimulated Progression of Human Non–Small Cell Lung Carcinoma Is Mediated by BCL2

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.

Artemin Stimulates Radio- and Chemo-resistance by Promoting TWIST1-BCL-2-dependent Cancer Stem Cell-like Behavior in Mammary Carcinoma Cells

“…Luciferase Reporter Assay-Luciferase reporter assay was performed as described previously (19) using TWIST1 (20) and BCL-2 (19) promoter constructs.…”

ARTEMIN synergizes with TWIST1 to promote metastasis and poor survival outcome in patients with ER negative mammary carcinoma

“…ARTN has been reported to promote mammary [7,8], endometrial [9], lung [10] and pancreatic [11] carcinoma progression. ARTN is an estrogen-regulated gene and it has been demonstrated that ARTN reduces the efficacy of anti-estrogens in ER+MC [8].…”

Prognostic significance of artemin and GFRα1 expression in laryngeal squamous cell carcinoma

“…Furthermore, the expression of ARTN was demonstrated to be significantly associated with high tumor stage and poor survival. In addition, previous studies have suggested that ARTN has a role in the development and progression of diverse human carcinoma (9,10,12,20–22). In pancreatic ductal adenocarcinoma, ARTN has been reported to be highly expressed compared with normal pancreases, and stimulates the invasiveness of pancreatic cancer cells (13).…”

“…Furthermore, the depletion of ARTN expression inhibits survival, invasion and anchorage-independent growth of both breast and endometrial cancer cells, while the forced expression of ARTN promotes these cellular behaviors (9,11). Molecularly, ARTN stimulates survival and anchorage-independent growth of human non-small cell lung cancer cells by upregulating BCL-2 expression (12). In addition, ARTN stimulates estrogen receptor-negative breast cancer cell growth, migration and metastasis by upregulating TWIST1 expression and activating the AKT pathway (21).…”