Abstract
This study is aimed at investigating the role and novel molecular mechanisms of galectin-1 in lung cancer progression. The role of galectin-1 in lung cancer progression was evaluated both in vitro and in vivo by short hairpin RNA (shRNA)-mediated knockdown of galectin-1 in lung adenocarcinoma cell lines. To explore novel molecular mechanisms underlying galectin-1-mediated tumor progression, we analyzed gene expression profiles and signaling pathways using reverse transcription PCR and Western blotting. A tissue microarray containing samples from patients with lung cancer was used to examine the expression of galectin-1 in lung cancer. We found overexpression of galectin-1 in non-small cell lung cancer (NSCLC) cell lines. Suppression of endogenous galectin-1 in lung adenocarcinoma resulted in reduction of the cell migration, invasion, and anchorage-independent growth in vitro and tumor growth in mice. In particular, COX-2 was downregulated in galectin-1-knockdown cells. The decreased tumor invasion and anchorage-independent growth abilities were rescued after reexpression of COX-2 in galectin-1-knockdown cells. Furthermore, we found that TGF-β1 promoted COX-2 expression through galectin-1 interaction with Ras and subsequent activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and NF-κB pathway. Galectin-1 knockdown sensitized lung cancer cells to platinum-based chemotherapy (cisplatin). In addition, galectin-1 and COX-2 expression was correlated with the progression of lung adenocarcinoma, and high clinical relevance of both proteins was evidenced (n = 47). p38 MAPK, ERK, and COX-2 activation are novel mediators for the galectin-1-promoted tumor progression and chemoresistance in lung cancer. Galectin-1 may be an innovative target for combined modality therapy for lung cancer.
Highlights
Lung cancer is the leading cause of cancer-associated death worldwide
We found that TGF-b1 promoted COX-2 expression through galectin-1 interaction with Ras and subsequent activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal–regulated kinase (ERK), and NF-kB pathway
Galectin-1 and COX-2 expression was correlated with the progression of lung adenocarcinoma, and high clinical relevance of both proteins was evidenced (n 1⁄4 47)
Summary
Lung cancer is the leading cause of cancer-associated death worldwide. Approximately, 85% of lung cancer is histologically classified as non–small cell lung cancerAuthors' Affiliations: 1Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, and Department of Education and Research, Taipei City Hospital; 2Institute of Anatomy and Cell Biology, National Yang-Ming University; 3Division of Urology, Department of Surgery, Tri-Service General Hospital and National Defense Medical Center; 4Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital; 5Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei; and 6Institute of Marine Biotechnology, National Taiwan Ocean University, Keelung, TaiwanNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).Ó2012 American Association for Cancer Research.(NSCLC; ref. 1). Lung cancer is the leading cause of cancer-associated death worldwide. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). The 5-year survival rate of most patients with advanced NSCLCs is only 9% to 15% [2]. EGF receptortyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, are commonly used for patients with advanced adenocarcinoma. Clinical reports show that only 10% of patients with NSCLCs respond to gefitinib or erlotinib [4, 5]. The development of novel molecular approaches is of particular importance for combined modality treatments of lung cancer
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