Chen Liang, Niu Wenyang, Zang Hong, Qiu Yudong
Department of Hepatobiliary Pancreatic Center, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, China.
Department of Hepatobiliary Surgery, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, #6 Hai'Er Xiang North Road, Nantong, 226001, Jiangsu Province, China.
Biochem Genet. 2024 Apr;62(2):814-830. doi: 10.1007/s10528-023-10451-4. Epub 2023 Jul 17.
DTX3L (Deltex E3 ubiquitin ligase 3 L) is an E3 ubiquitin ligase, a member of the deltex family. It is also known as B-lymphoma and BAL-associated protein (BBAP). DTX3L has been proven to play an important role in various tumor development; however, its role in pancreatic cancer remains unknown. So, we analyzed the DTX3L expression in pancreatic cancer based on the TCGA database and verified it in our samples by qRT‑PCR and western blot. We identified that DTX3L was highly expressed in pancreatic cancer, and its expression level was significantly negatively correlated with patients' survival. Using CCK8, colony formation, transwell, and wound healing assays, we found that upregulated DTX3L promotes pancreatic cancer cell proliferation, invasion, and migration. Mechanically, DTX3L combined with EGFR (epidermal growth factor receptor) and prevented the ubiquitination degradation of it. Upregulated EGFR activated the FAK/PI3K/Akt pathway and promoted the progression of pancreatic cancer. Moreover, we found that DTX3L can weaken pancreatic cancer cells' sensitivity to chemotherapy using the orthotopic implant tumor model. In conclusion, DTX3L accelerates pancreatic cancer progression by EGFR dependent FAK/PI3K/Akt pathway activation and may become a potential target for pancreatic cancer treatment.
DTX3L（Deltex E3泛素连接酶3L）是一种E3泛素连接酶，属于德尔塔蛋白家族成员。它也被称为B淋巴瘤和BAL相关蛋白（BBAP）。DTX3L已被证明在各种肿瘤发展中发挥重要作用；然而，其在胰腺癌中的作用尚不清楚。因此，我们基于TCGA数据库分析了DTX3L在胰腺癌中的表达，并通过qRT-PCR和蛋白质免疫印迹在我们的样本中进行了验证。我们发现DTX3L在胰腺癌中高表达，其表达水平与患者生存率显著负相关。使用CCK8、集落形成、Transwell和伤口愈合实验，我们发现上调DTX3L可促进胰腺癌细胞增殖、侵袭和迁移。机制上，DTX3L与表皮生长因子受体（EGFR）结合并阻止其泛素化降解。上调的EGFR激活FAK/PI3K/Akt通路并促进胰腺癌进展。此外，我们使用原位植入肿瘤模型发现DTX3L可削弱胰腺癌细胞对化疗的敏感性。总之，DTX3L通过EGFR依赖的FAK/PI3K/Akt通路激活加速胰腺癌进展，可能成为胰腺癌治疗的潜在靶点。
