Hemmung von YB-1 als neuer therapeutischer Ansatz zur Verringerung der Expression von EGFR, HER-2 und IGF-IR beim Ösophaguskarzinom

Abstract

The Y-box binding protein-1 (YB-1) is an oncogenic transcription factor that is highly expressed in many malignant tissues, including cancers of the breast and non-small cell lung cancer. Although these findings suggest an involvement of YB-1 in the progression of malignancies, so far no data as to its role in esophageal cancer (EC) are available. Molecular profiling studies have identified HER-2, Epidermal Growth Factor Receptor (EGFR) and Insulin-like-Growth-Factor I Receptor (IGF-IR) as co-factors in tumor progression. Inhibition of YB-1 leads to suppression of EGFR and HER-2 in breast cancer. Also, EGFR, IGF-IR and HER-2 are highly expressed in EC and associated with tumor growth and poor survival. The aim of this study was to evaluate the impact of YB-1 in EC and its influence on different protein tyrosine kinase receptor expression. For this, a tumor tissue microarray (TMA) was constructed from 293 primary esophageal carcinomas, 146 corresponding lymph nodes and 47 distant metastases. The TMA slides were analysed by immunhistochemistry for YB-1 expression.

Overexpression of YB-1 was seen in 141/276 cases. Albeit a significant relationship between YB-1 expression and survival was absent, there was a 67 % concordance of YB-1 positivity in primary tumors and corresponding lymph node (p = 0.34). The overlap between YB-1 positivity in primary tumors and distant metastasis was even higher (p = 0.07). YB-1 was simultaneously expressed with IGF-1R, EGFR and proliferation marker Ki67. In 51 % of patients YB-1 and HER-2 were coexpressed. Cell line experiments revealed a synergistic growth inhibition by co-targeting IGF-IR and HER-2. Using three different EC cell lines including one deriving from a lymph node metastasis, downregulation of endogenous YB-1 led to a reduction of proliferation of EC cell growth of more than 50 %. Efficiency of YB-1 knock down was assessed by quantitative RT-PCR, demonstrating a 70–80 % decrease of YB-1 transcript numbers. Furthermore, loss of YB-1 expression resulted in a reduced HER-2 and EGFR expression. Treatment with gemcitabine, cisplatin and herceptin in YB-1 knock down cells reduced cell proliferation more effective than in controll cells.

HER-2, EGFR and IGF-1R are essential for EC tumor growth and progression. Targeting YB-1 is an attractive approach to inhibit simultaneously the expression of most important growth factor receptors. Therefore, YB-1 could be a novel therapeutic target for esophageal tumor suppression.