Unraveling the molecular tumor-promoting regulation of cofilin-1 in pancreatic cancer
Autor: | Hans A. Kestler, Jan Sperveslage, Sandra Kirchhoff, Bence Sipos, Julian D. Schwab, Nensi Ikonomi, Ramona Diels, Thomas M. Gress, Robin Szekely, Marina Tatura, Silke D. Werle, Malte Buchholz |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Cancer Research
Pancreatic neoplasms pancreatic cancer lcsh:RC254-282 Article Boolean networks 03 medical and health sciences 0302 clinical medicine Cofilin 1 Pancreatic cancer medicine Molecular targeted therapy ddc:610 Bauchspeicheldrüsenkrebs STAT3 Transcription factor 030304 developmental biology 0303 health sciences biology Pancreas Cancer cofilin-1 CD44 Actin remodeling modeling predicting therapeutic targets medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 3. Good health Actin depolymerizing factors Oncology 030220 oncology & carcinogenesis Cofilin Cancer research biology.protein STAT protein Boolesches Netz Aurora Kinase A molecular mechanism Therapie DDC 610 / Medicine & health |
Zdroj: | Cancers Volume 13 Issue 4 Cancers, Vol 13, Iss 725, p 725 (2021) |
Popis: | 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. publishedVersion |
Databáze: | OpenAIRE |
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