Table_1_ECT2 Increases the stability of EGFR and Tumorigenicity by Inhibiting Grb2 Ubiquitination in Pancreatic Cancer.docx

The poor prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is associated with the invasion and metastasis of tumor cells. Epithelial cell transforming 2 (ECT2) is a guanine nucleotide exchange factor (GEF) of the Rho family of GTPases. It has also been reported that upregulation of ECT2 in pancreatic cancer, but the role and mechanism of ECT2 have not been previously determined. We found that ECT2 was significantly elevated in PDAC tissues and cells, correlated with more advanced AJCC stage, distant metastases, and overall survival of patients with PDAC. Inhibition and overexpression tests showed that ECT2 promoted proliferation, migration and invasion in vitro, and promoted tumor growth and metastasis in vivo. We determined that ECT2 was involved in the post-translational regulation of Grb2. ECT2 inhibited the degradation of Grb2 through deubiquitination. Furthermore, knockdown of ECT2 downregulated EGFR levels by accelerating EGFR degradation. EGF stimulation facilitated the formation of ECT2-Grb2 complex. Overall, our findings indicated that ECT2 could be used as a promising new therapeutic candidate for PDAC.

胰腺导管腺癌（PDAC）患者预后不佳，与肿瘤细胞的侵袭和转移密切相关。上皮细胞转化因子2（ECT2）是Rho家族GTPases的鸟苷酸交换因子（GEF）。已有研究表明，在胰腺癌中ECT2的上调，但其作用及机制尚未得到明确。我们发现在PDAC组织和细胞中ECT2显著升高，与AJCC分期更晚、远处转移及PDAC患者的总生存期相关。抑制和过表达实验表明，ECT2在体外促进细胞增殖、迁移和侵袭，并在体内促进肿瘤生长和转移。我们确定ECT2参与了Grb2的翻译后调控。ECT2通过去泛素化抑制Grb2的降解。此外，ECT2的敲低通过加速EGFR的降解降低了EGFR的水平。EGF刺激促进了ECT2-Grb2复合物的形成。总体而言，我们的研究结果表明ECT2可作为PDAC治疗的潜在新靶点。