Inhibition of Yb-1 As a Novel Approach to Decrease the Expression of Egfr, Her-2 and Igf-1r in Esophageal Cancer
Sabrina Thieltges*1, Tanya Kalinina1, Uta Reichelt2, Jussuf T. Kaifi1, Yogesh K. Vashist1, Paulus G. Schurr1, Peter R. Mertens3, Ronald Simon2, Jakob R. Izbicki1, Emre F. Yekebas1
1Department of General-, Visceral- and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany; 2Department of Pathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany; 3Department of Nephrology and Immunology, University Hospital Aachen, Aachen, Germany
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, non-small cell lung cancer, ovarian adenocarcinoma and prostata 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. Different molecular profiling studies have identified HER-2, Epidermal Growth Factor Receptor (EGFR) and Insulin-like-Growth-Factor I Receptor (IGF-IR) as important 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 reason, a tumor tissue microarray (TMA) was constructed from 293 primary ECs (130 adenocarcinomas and 163 squamous cell carcinomas), 146 corresponding lymph nodes and 47 distant metastases. The TMA slides were analysed by immunhistochemistry for YB-1 expression.YB-1 was not detected in control tissues, including normal esophageal tissue. Overexpression of YB-1 was seen in 141/276 cases (51,1%) without difference between adeno- and squamous cell carcinoma. There was a 67% concordance of YB-1 positivity in primary tumors and corresponding lymph node (p=0,34) and metastasis (p=0,07). Nevertheless, no significant relationship between YB-1 expression and survival was seen. YB-1 was simultaneously expressed with IGF-1R, EGFR and proliferation marker Ki67. The Fishers exact test showed that coexpression was significant. In 51% of patients YB-1 and HER-2 were coexpressed. A synergistic growth inhibition was shown by IGF-IR and HER-2 co-targeting in EC cell lines. These results suggest that YB-1 can transcriptionally induce EGFR, IGF-1R and HER-2. Using three different EC cell lines including one lymph node metastasis cell line, downregulation of endogenous YB-1 led to a reduction of proliferation of EC cell growth of more than 50%. Ongoing experiments knocking down YB-1 will clarify its interference with protein tyrosine kinase receptor expression.EGFR, HER-2 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.
