Y-Box Binding Protein-1-Mediated Antiproliferative Effects in Esophageal Cancer
Sabrina Thieltges*, Tatyana Kalinina, Yogesh K. Vashist, Emre F. Yekebas, Jakob R. Izbicki
Department of General-, Visceral- and Thoracic surgery, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
In a recent study we identified the impact of the oncogenic transcription factor Y-box binding protein-1 (YB-1) in esophageal cancer and its influence on different protein tyrosine kinase receptor expression. Expression of HER-2, Epidermal Growth Factor Receptor (EGFR) and Insulin-like-Growth-Factor 1 Receptor (IGF-1R) is associated with tumor growth and poor survival. Having demonstrated that YB-1 was simultaneously expressed with these growth factor receptors in esophageal cancer, the aim of this study was to evaluate the effect of inhibition of YB-1.For this reason, three esophageal cancer cell lines were stably transfected with YB-1 specific siRNA. Efficacy of YB-1 knock-down was assessed by quantitative reverse transcription PCR and immunoblotting. Depletion of YB-1 lead to a decrease of HER-2 mRNA expression by >90% in comparison to control clones. YB-1 knockdown suppressed mRNA expression of IGF-1R by 71 to 75%. In immunoblot analysis, reduction of YB-1 expression resulted in a simultaneous decrease of EGFR and HER-2 expression. Antiproliferative effects of YB-1 siRNA in esophageal cancer cells was detected by MTT assay. Downregulation of YB-1 in esophageal cancer cell cultures affected antibody-induced cell growth inhibition and sensibilized cells to drug treatment. Cisplatin treatment resulted in lowest proliferation rates. In YB-1 knockdown cells, inhibition of cell proliferation to 50% (IC50) was achieved with 5 μM cisplatin in comparison to >20 μM in control cells. Even the antiproliferative effects of herceptin are intensified by use of YB-1-specific siRNA, showing up to 60% lower cell proliferation rates in comparison to control cells. The presented results indicate YB-1 as a novel and auspicious therapeutic target for esophageal tumor suppression aimed at overcoming tumor aggressiveness and multi-drug resistance. Future research activities should especially focus on the molecular mechanisms of YB-1-mediated antiproliferative effects and its interaction with different growth factor receptors.
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