Snail promotes CXCR2 ligand-dependent tumor progression in non-small cell lung carcinoma.

Abstract

PURPOSE:

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).

EXPERIMENTAL DESIGN:

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.

CONCLUSION:

Snail upregulation plays a role in human NSCLC by promoting tumor progression mediated by CXCR2 ligands.

• Authors: Jane Yanagawa, Tonya C Walser, Li X Zhu, Longsheng Hong, Michael C Fishbein, Vei Mah, David Chia, Lee Goodglick, David A Elashoff, Jie Luo, Clara E Magyar, Mariam Dohadwala, Jay M Lee, Maie A St John, Robert M Strieter, Sherven Sharma, Steven M Dubinett
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 22 Pg. 6820-9 (Nov 15 2009) ISSN: 1557-3265 [Electronic] United States
• PMID: 19887480 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Ligands
• Receptors, Interleukin-8B
• Snail Family Transcription Factors
• Transcription Factors

Topics

• Animals
• Cadherins (metabolism)
• Carcinoma, Non-Small-Cell Lung (metabolism, pathology)
• Disease Progression
• Female
• Gene Expression Profiling
• Humans
• Immunohistochemistry (methods)
• Ligands
• Lung Neoplasms (metabolism, pathology)
• Mice
• Mice, SCID
• Oligonucleotide Array Sequence Analysis
• Receptors, Interleukin-8B (metabolism)
• Snail Family Transcription Factors
• Transcription Factors (metabolism)
• Transcription, Genetic