Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer
Open Access
- 10 February 2021
- Vol. 13 (4), 725
- https://doi.org/10.3390/cancers13040725
Abstract
Cofilin-1 (CFL1) overexpression in pancreatic cancer correlates with high invasiveness and shorter survival. Besides a well-documented role in actin remodeling, additional cellular functions of CFL1 remain poorly understood. Here, we unraveled molecular tumor-promoting functions of CFL1 in pancreatic cancer. For this purpose, we first show that a knockdown of CFL1 results in reduced growth and proliferation rates in vitro and in vivo, while apoptosis is not induced. By mechanistic modeling we were able to predict the underlying regulation. Model simulations indicate that an imbalance in actin remodeling induces overexpression and activation of CFL1 by acting on transcription factor 7-like 2 (TCF7L2) and aurora kinase A (AURKA). Moreover, we could predict that CFL1 impacts proliferation and apoptosis via the signal transducer and activator of transcription 3 (STAT3). These initial model-based regulations could be substantiated by studying protein levels in pancreatic cancer cell lines and human datasets. Finally, we identified the surface protein CD44 as a promising therapeutic target for pancreatic cancer patients with high CFL1 expression.Funding Information
- FP7 Ideas: European Research Council (602783)
- Deutsche Forschungsgemeinschaft (SFB 1074 project Z1, GRK 2254 HEIST, Clinical Research Unit 325, subproject A2)
- Bundesministerium für Bildung und Forschung (Forschungskern SyStaR, e:Med, SYMBOL-HF, e:Med, conFim)
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