Research Paper Volume 12, Issue 1 pp 53—69
FHL3 promotes pancreatic cancer invasion and metastasis through preventing the ubiquitination degradation of EMT associated transcription factors
- 1 The First People's Hospital of Xiaoshan Hangzhou, Zhejiang 311000, China
- 2 Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
- 3 Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, China
- 4 Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei Province, China
Received: October 14, 2019 Accepted: November 20, 2019 Published: January 13, 2020
https://doi.org/10.18632/aging.102564How to Cite
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is intractable due to its strong invasiveness and metastatic ability. Epithelial-mesenchymal transition (EMT) is the pivotal driver of tumor invasion and metastasis. The four-and-a-half LIM domain (FHL) family is involved in regulating transforming growth factor (TGF)-β and Ras signaling, which might control the EMT process. In this study, we found that higher expression of four-and-a-half LIM domains 3 (FHL3) predicted poor prognosis in PDAC. The decreasing of FHL3 changed the EMT phenotype by blocking the TGFβ/Atk/GSK3β/ubiquitin pathways. Interestingly, the GSK3β inhibitor could abrogate the role of FHL3 in the regulation of snail1 and twist1 expression, which implied that GSK3β plays a pivotal role in the FHL3-mediated EMT process. Furthermore, we found that FHL3 can directly bind to GSK3β, which weakened the interaction between GSK3β and snail1/twist1. We also found that the LIM-3 domain of FHL3 was required for the binding of FHL3 to GSK3β. Collectively, our study implied that FHL3, as a binding partner of GSK3β, promoted tumor metastasis in PDAC through inhibiting the ubiquitin-degradation of snail1 and twist1.