Snail promotes CXCR2 ligand-dependent tumor progression in non-small cell lung carcinoma.
OBJECTIVE
As a transcriptional repressor of E-cadherin, Snail has predominantly been associated with epithelial-mesenchymal transition, invasion, and metastasis. However, other important Snail-dependent malignant phenotypes have not been fully explored. Here, we investigate the contributions of Snail to the progression of non-small cell lung cancer (NSCLC).


METHODS
Immunohistochemistry was done to quantify and localize Snail in human lung cancer tissues, and tissue microarray analysis was used to correlate these findings with survival. NSCLC cell lines gene-modified to stably overexpress Snail were evaluated in vivo in two severe combined immunodeficiency murine tumor models. Differential gene expression between Snail-overexpressing and control cell lines was evaluated using gene expression microarray analysis.


RESULTS
Snail is upregulated in human NSCLC tissue, and high levels of Snail expression correlate with decreased survival (P < 0.026). In a heterotopic model, mice bearing Snail-overexpressing tumors developed increased primary tumor burden (P = 0.008). In an orthotopic model, mice bearing Snail-overexpressing tumors also showed a trend toward increased metastases. In addition, Snail overexpression led to increased angiogenesis in primary tumors as measured by MECA-32 (P < 0.05) positivity and CXCL8 (P = 0.002) and CXCL5 (P = 0.0003) concentrations in tumor homogenates. Demonstrating the importance of these proangiogenic chemokines, the Snail-mediated increase in tumor burden was abrogated with CXCR2 blockade. Gene expression analysis also revealed Snail-associated differential gene expression with the potential to affect angiogenesis and diverse aspects of lung cancer progression.


CONCLUSIONS
Snail upregulation plays a role in human NSCLC by promoting tumor progression mediated by CXCR2 ligands.
Yanagawa
Jane
J
Lung Cancer Research Program, Division of Pulmonary and Critical Care Medicine, 10833 Le Conte Avenue, 37-131 CHS, Los Angeles, CA 90095-1690, USA.
Walser
Tonya C
TC
Zhu
Li X
LX
Hong
Longsheng
L
Fishbein
Michael C
MC
Mah
Vei
V
Chia
David
D
Goodglick
Lee
L
Elashoff
David A
DA
Luo
Jie
J
Magyar
Clara E
CE
Dohadwala
Mariam
M
Lee
Jay M
JM
St John
Maie A
MA
Strieter
Robert M
RM
Sharma
Sherven
S
Dubinett
Steven M
SM
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D015820:Cadherins; D008024:Ligands; D023063:Receptors, Interleukin-8B; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors