Artemin-stimulated progression of human non-small cell lung carcinoma is mediated by BCL2.
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.
Tang
Jian-Zhong
JZ
Liggins Institute, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Kong
Xiang-Jun
XJ
Kang
Jian
J
Fielder
Graeme C
GC
Steiner
Michael
M
Perry
Jo K
JK
Wu
Zheng-Sheng
ZS
Yin
Zhinan
Z
Zhu
Tao
T
Liu
Dong-Xu
DX
Lobie
Peter E
PE
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
C490886:ARTN protein, human; D004338:Drug Combinations; D007797:Laminin; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011509:Proteoglycans; D019253:Proto-Oncogene Proteins c-bcl-2; C059485:matrigel; D003094:Collagen