The role of galectin-1 and galectin-3 in COX-2 activation, chemoresistance and stemness of lung cancer
| Autor: | Ling-Yen Chung, 鐘令雁 |
|---|---|
| Rok vydání: | 2012 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 100 Lung cancer is the leading cause of cancer-related deaths worldwide. The 5-year-survival rate of most patients with advanced non-small cell lung cancer (NSCLC) is only 9 to 15%. Combination cytotoxic chemotherapy results in a modest increase in survival at the cost of high toxicity. Targeting therapeutic approaches have been indicated to improve standard chemotherapy. EGFR inhibitors have been commonly used in lung cancer treatment. However, clinical reports show that only 10% of patients with NSCLC respond to EGFR inhibitors. Therefore, the development of novel molecular approaches is of particular importance for combined modality treatments of lung cancer. Our studies provide insight into influence of galectin-1 and galectin-3, which are increasing recognized as important factors of regulatory proteins, in lung cancer development. I found highly expressed galectin-1 in 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 migration, invasion and anchorage-independent growth abilities were rescued after reexpression of COX-2 in galectin-1 knockdown cells. Furthermore, I found that TGF-1 promoted COX-2 transcription through galectin-1 interaction with Ras and subsequent activation of p38 MAPK, ERK and NF-B pathway. In addition, suppression of galectin-1 sensitized lung cancer cells to platinum-based chemotherapy (cisplatin). I found that galectin-1 and COX-2 expression were correlated with the progression of lung adenocarcinoma, and high clinical relevance of both proteins was evidenced in NSCLC (n = 82). These findings suggest that 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 of lung cancer. The prognosis of lung cancer remains poor as a result of the high recurrence rates and low response to irradiation and chemotherapy. It has been indicated that cancer stem cells (CSCs) comprise a rare subpopulation of cells in tumors that are proposed to be responsible for high recurrence rates and resistance to chemotherapy. I found a novel candidate stemness-maintaining molecule, galectin-3 in lung CSCs. Enriched H1299-CSCs highly expressed the stem/progenitor cell markers such as Oct-4, SOX-2 and Nanog. The expression of galectin-3 was robustly increased in primary and secondary spheres. Upon suppression of galectin-3 in either parental H1299 or H1299-CSCs, sphere forming ability and tumorigenicity were significantly decreased. The effects of galectin-3 on stemness were also investigated in A549 cells, which harbor p53 wild-type. Enriched A549-CSCs upon overexpression of galectin-3 decreased in epithelial marker, E-cadherin, while increased in mesenchymal marker, vimentin, and stemness-related genes. To examine a novel molecular mechanisms regulated by galectin-3 in maintaining the stem-like properties, protein microarrays were performed. I found that protein levels of GM-CSF were elevated in H1299-CSCs and reduced in galecitin-3-inhibited cells. Our finding revealed a role for galectin-3 in maintaining stem-like properties and tumorigenicity of lung CSCs, suggesting that targeting galectin-3 signaling may provide a new strategy for lung cancer treatment by eliminating cancer stem-like cells. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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