Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China.
Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China.
Cancer Lett. 2019 Jun 1;451:48-57. doi: 10.1016/j.canlet.2019.02.043. Epub 2019 Mar 6.
WT1 associated protein (WTAP), playing an important role in several malignancies owing to its complex function in transcriptional and post-transcriptional regulation, is an independent prognostic indicator for pancreatic cancer (PC). However, its specific role and underlying mechanism in PC remain unclear. In the present study, we found that WTAP could promote migration/invasion and suppress chemo-sensitivity to gemcitabine in PC. Further mechanical investigation revealed that WTAP could bind to and stabilize Fak mRNA which in turn activated the Fak-PI3K-AKT and Fak-Src-GRB2-Erk1/2 signaling pathways. In addition, GSK2256098, a specific Fak inhibitor, could reverse WTAP-mediated chemo-resistance to gemcitabine and metastasis in PC. Taken together, Fak inhibitor might be a promising therapeutic option for PC patients with WTAP overexpression.
WT1 相关蛋白（WTAP）在转录和转录后调控中发挥着复杂的作用，因此在多种恶性肿瘤中扮演着重要角色，是胰腺癌（PC）的独立预后指标。然而，其在 PC 中的具体作用和潜在机制尚不清楚。在本研究中，我们发现 WTAP 可促进 PC 细胞的迁移/侵袭，并抑制对吉西他滨的化疗敏感性。进一步的机制研究表明，WTAP 可与 Fak mRNA 结合并使其稳定，进而激活 Fak-PI3K-AKT 和 Fak-Src-GRB2-Erk1/2 信号通路。此外，Fak 的特异性抑制剂 GSK2256098 可逆转 WTAP 介导的吉西他滨化疗耐药和 PC 转移。综上所述，Fak 抑制剂可能是 WTAP 过表达的 PC 患者有前景的治疗选择。
