To clarify the mechanism that C terminal fragments of EGFR ligand cause nuclear export of transcriptional repressors

BCL 6是一种转录抑制因子，在淋巴细胞分化和淋巴瘤发生中具有重要作用，但在胃癌中的表达尚未见报道。在本研究中，我们研究了BCL 6在胃癌中的功能。TPA处理导致BCL 6降解和细胞周期蛋白D2上调。这种现象被HB-EGF-CTF（pro-HB-EGF的C-末端片段）的核转位抑制所抑制。HB-EGF-CTF核转位导致BCL 6与HB-EGF-CTF相互作用并向核输出，然后通过泛素/蛋白酶体途径降解BCL 6。实时RT. PCR和靶向BCL 6的siRNA显示BCL 6抑制细胞周期蛋白D2的表达。我们的数据表明，BCL 6与核转位的HB-EGF-CTF相互作用，BCL 6的核输出和降解诱导细胞周期蛋白D2上调。我们进行了BCL 6，HB-EGF和cyclin D2在人胃癌中的免疫组化分析。在HB-EGF阳性的胃癌中，BCL 6和cyclin D2也呈负相关。HB-EGF-CTF引起的BCL 6降解也可能诱导人胃癌细胞中cyclin D2的表达。抑制HB-EGF-CTF核转位和维持BCL 6的功能在胃癌进展的调控中具有重要意义。

BCL6 is a transcriptional repressor that has important functions in lymphocyte differentiation and lymphomagenesis, but there have been no reports of BCL6 expression in gastric cancers. In the present study, we investigated the BCL6 function in gastric cancers. Treatment with TPA resulted in BCL6 degradation and cyclin D2 upregulation. This phenomenon was inhibited by the suppression of the nuclear translocation of HB-EGF-CTF(C-terminal fragment of pro-HB-EGF). The HB-EGF-CTF nuclear translocation leads to the interaction of BCL6 with HB-EGF-CTF and the nuclear export of BCL6, and after that BCL6 degradation was mediated by ubiquitin/proteasome pathway. Real-time RT. PCR and siRNA targeting BCL6 revealed that BCL6 suppresses cyclin D2 expression. Our data indicate that BCL6 interacts with nuclear-translocated HB-EGF-CTF and that the nuclear export and degradation of BCL6 induces cyclin D2 upregulation. We performed immunohistochemical analyses of BCL6, HB-EGF and cyclin D2 in human 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 might induce cyclin D2 expression in human gastric cancers. Inhibition of HB-EGF-CTF nuclear translocation and maintenance of BCL6 function are important for the regulation of gastric cancer progression.