S2034 CEA Increases Metastatic Potential of CRC Cells By Targeting Multiple Signaling Pathways

Abstract

BCL6 and nuclear translocation of HB-EGF-CTF in gastric cancers. Method: We examined BCL6 and cyclinD2 expression level under the 12-0-tetradecanoylphorbor-13-acetate (TPA) stimulation. KB-R7785 was used to suppress HB-EGF-CTF nuclear translocation. We also investigated the interaction and translocation of BCL6 with HB-EGF-CTF by using immunofluorescence microscopy and immunoprecipitation. Furthermore, we immunohistochemically studied 100 surgical specimens of advanced gastric cancers to analyze the expression of HB-EGF, BCL6, and cyclin D2. Results: TPA treatment resulted in BCL6 degradation and cyclin D2 up-regulation. This phenomenon was inhibited by the suppression of the nuclear translocation of HB-EGF-CTF. The HB-EGF-CTF nuclear translocation lead to the interaction of BCL6 with HB-EGF-CTF and the nuclear export of BCL6, and the ubiquitin/proteasome pathway mediated the BCL6 degradation. siRNA targeting BCL6 revealed that the upregulation of cyclin D2 depends on BCL6 degradation. BCL6 interacts with nuclear translocated HB-EGF-CTF and the nuclear export and degradation of BCL6 (caused by this interaction and the ubiquitin/proteasome pathway) induces cyclin D2 up-regulation. In human gastric cancer tissues, BCL6 expression is associated with differentiated gastric cancers. The inverse correlation between BCL6 and cyclin D2 was also found in HB-EGF-positive human gastric cancers. BCL6 degradation caused by the HB-EGF-CTF also induced cyclin D2 expression In Vivo (human cancer tissues). Conclusion: Inhibition of HB-EGF-CTF nuclear translocation and the resulting maintenance of BCL6 function are important for the regulation of gastric cancer progression.