肿瘤坏死因子受体相关因子-6在胰腺癌肿瘤发生中的作用

The Role of Tumor Necrosis Factor Receptor-Associated Factor-6 in Tumorigenesis of Pancreatic Cancer

肿瘤坏死因子受体相关因子-6(TRAF6)在胰腺癌中过度表达并参与调节肿瘤细胞的生长,然而其具体机制尚不清楚。本研究旨在考察TRAF6在胰腺癌肿瘤发生中的作用。研究显示,敲低TRAF6的表达显著抑制人胰腺癌细胞系PANC-1的YAP的活性。敲低TRAF6的表达显著抑制YAP的3个靶基因(Cyr61,Cyclin E和CTGF)的表达。并且,TRAF6的下调显著降低了YAP的蛋白水平。敲低YAP的表达消除了TRAF6对胰腺癌细胞迁移和集落形成的促进作用。免疫荧光观察到PANC-1细胞中TRAF6和MST1的共定位。在GST pull-down测定实验中发现在PANC-1细胞中GST-TRAF6与MST可形成复合物。PANC-1细胞中TRAF6的过表达以剂量依赖性方式降低MST蛋白水平,而敲低TRAF6则显著增加MST蛋白的表达水平。总之,本研究表明,TRAF6通过YAP信号通路调节胰腺癌的进展。TRAF6与MST之间存在交互作用,并且TRAF6的上调可促进MST的降解,从而促进胰腺癌进展。因此,TRAF6有望成为胰腺癌的新治疗靶标。

Tumor necrosis factor receptor-associated factor-6(TRAF6)is overexpressed in pancreatic cancer and is involved in the regulation of tumor cell growth.However,the specific mechanism remains unclear.This study was designed to investigate the role of TRAF6 in the development of pancreatic cancer.Studies showed that knockdown of TRAF6 expression significantly inhibited YAP activity in the human pancreatic cancer cell line PANC-1.Knockdown of TRAF6 expression significantly inhibited the expression of the three target genes of YAP(Cyr61,Cyclin E and CTGF).Moreover,down-regulation of TRAF6 significantly reduced the protein level of YAP.Knockdown of YAP expression abolished the promotion of TRAF6 on pancreatic cancer cell migration and colony formation.Colocalization of TRAF6 and MST1 in PANC-1 cells was observed by immunofluorescence.GST-TRAF6 and MST were found to form complexes in PANC-1 cells in GST pull-down assays.Overexpression of TRAF6 in PANC-1 cells reduced MST protein levels in a dose-dependent manner,while knockdown of TRAF6 significantly increased MST protein expression levels.In conclusion,this study demonstrates that TRAF6 regulates the progression of pancreatic cancer through the YAP signaling pathway.There is an interaction between TRAF6 and MST,and upregulation of TRAF6 promotes the degradation of MST,thereby promoting pancreatic cancer progression.Therefore,TRAF6 is expected to be a new therapeutic target for pancreatic cancer.