Bibliographic Details
| Title: |
Smad4 regulates TGF-β1-mediated hedgehog activation to promote epithelial-to-mesenchymal transition in pancreatic cancer cells by suppressing Gli1 activity |
| Authors: |
Hangcheng Guo, Zujian Hu, Xuejia Yang, Ziwei Yuan, Mengsi Wang, Chaoyue Chen, Lili Xie, Yuanyuan Gao, Wangjian Li, Yongheng Bai, Chunjing Lin |
| Source: |
Computational and Structural Biotechnology Journal, Vol 23, Iss , Pp 1189-1200 (2024) |
| Publisher Information: |
Elsevier, 2024. |
| Publication Year: |
2024 |
| Collection: |
LCC:Biotechnology |
| Subject Terms: |
Pancreatic cancer, Epithelial-mesenchymal transition (EMT), TGF-β1, Smad4, Gli1, Hedgehog signaling, Biotechnology, TP248.13-248.65 |
| More Details: |
Pancreatic cancer (PC) is an aggressive and metastatic gastrointestinal tumor with a poor prognosis. Persistent activation of the TGF-β/Smad signaling induces PC cell (PCC) invasion and infiltration via epithelial-to-mesenchymal transition (EMT). Hedgehog signaling is a crucial pathway for the development of PC via the transcription factors Gli1/2/3. This study aimed to investigate the underlying molecular mechanisms of action of hedgehog activation in TGF-β1-triggered EMT in PCCs (PANC-1 and BxPc-3). In addition, overexpression and shRNA techniques were used to evaluate the role of Smad4 in TGF-β1-treated PCCs. Our data showed that TGF-β1 promoted PCC invasion and infiltration via Smad2/3-dependent EMT. Hedgehog-Gli signaling axis in PCCs was activated upon TGF-β1 stimulation. Inhibition of hedgehog with cyclopamine effectively antagonized TGF-β1-induced EMT, thereby suggesting that the hedgehog signaling may act as a downstream cascade signaling of TGF-β1. As a key protein that assists the nuclear translocation of Smad2/3, Smad4 was highly expressed in PANC-1 cells, but not in BxPc-3 cells. Conversely, Gli1 expression was low in PANC-1 cells, but high in BxPc-3 cells. Furthermore, knockdown of Smad4 in PANC-1 cells by shRNA inhibited TGF-β1-mediated EMT and collagen deposition. Overexpression of Smad4 did not affect TGF-β1-mediated EMT due to the lack of significant increase in nuclear expression of Smad4. Importantly, Gli1 activity was upregulated by Smad4 knockdown in PANC-1 cells and downregulated by Smad4 overexpression in BxPc-3 cells, indicating that Gli1 may be a negative target protein downstream of Smad4. Thus, Smad4 regulates TGF-β1-mediated hedgehog activation to promote EMT in PCCs by suppressing Gli1 activity. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2001-0370 |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S2001037024000631; https://doaj.org/toc/2001-0370 |
| DOI: |
10.1016/j.csbj.2024.03.010 |
| Access URL: |
https://doaj.org/article/d9af0ac656924a8a9c44b7a043c4c60d |
| Accession Number: |
edsdoj.9af0ac656924a8a9c44b7a043c4c60d |
| Database: |
Directory of Open Access Journals |
