Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer
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 pancreati...
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| Format: | Article |
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MDPI AG
2021-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/4/725 |
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| author | Silke D. Werle Julian D. Schwab Marina Tatura Sandra Kirchhoff Robin Szekely Ramona Diels Nensi Ikonomi Bence Sipos Jan Sperveslage Thomas M. Gress Malte Buchholz Hans A. Kestler |
| author_facet | Silke D. Werle Julian D. Schwab Marina Tatura Sandra Kirchhoff Robin Szekely Ramona Diels Nensi Ikonomi Bence Sipos Jan Sperveslage Thomas M. Gress Malte Buchholz Hans A. Kestler |
| author_sort | Silke D. Werle |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T04:52:11Z |
| format | Article |
| id | doaj.art-a0ac6d75fcf8434986f2d9f33d96606c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T04:52:11Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a0ac6d75fcf8434986f2d9f33d96606c2023-12-03T13:09:55ZengMDPI AGCancers2072-66942021-02-0113472510.3390/cancers13040725Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic CancerSilke D. Werle0Julian D. Schwab1Marina Tatura2Sandra Kirchhoff3Robin Szekely4Ramona Diels5Nensi Ikonomi6Bence Sipos7Jan Sperveslage8Thomas M. Gress9Malte Buchholz10Hans A. Kestler11Institute of Medical Systems Biology, Ulm University, 89081 Ulm, GermanyInstitute of Medical Systems Biology, Ulm University, 89081 Ulm, GermanyDepartment of Gastroenterology, Endocrinology and Metabolism, Philipps-University Marburg, 35043 Marburg, GermanyDepartment of Gastroenterology, Endocrinology and Metabolism, Philipps-University Marburg, 35043 Marburg, GermanyInstitute of Medical Systems Biology, Ulm University, 89081 Ulm, GermanyDepartment of Gastroenterology, Endocrinology and Metabolism, Philipps-University Marburg, 35043 Marburg, GermanyInstitute of Medical Systems Biology, Ulm University, 89081 Ulm, GermanyInstitute of Pathology, University of Tübingen, 72076 Tübingen, GermanyInstitute of Pathology, University of Tübingen, 72076 Tübingen, GermanyDepartment of Gastroenterology, Endocrinology and Metabolism, Philipps-University Marburg, 35043 Marburg, GermanyDepartment of Gastroenterology, Endocrinology and Metabolism, Philipps-University Marburg, 35043 Marburg, GermanyInstitute of Medical Systems Biology, Ulm University, 89081 Ulm, GermanyCofilin-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.https://www.mdpi.com/2072-6694/13/4/725pancreatic cancercofilin-1modelingmolecular mechanismBoolean networkspredicting therapeutic targets |
| spellingShingle | Silke D. Werle Julian D. Schwab Marina Tatura Sandra Kirchhoff Robin Szekely Ramona Diels Nensi Ikonomi Bence Sipos Jan Sperveslage Thomas M. Gress Malte Buchholz Hans A. Kestler Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer Cancers pancreatic cancer cofilin-1 modeling molecular mechanism Boolean networks predicting therapeutic targets |
| title | Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer |
| title_full | Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer |
| title_fullStr | Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer |
| title_full_unstemmed | Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer |
| title_short | Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer |
| title_sort | unraveling the molecular tumor promoting regulation of cofilin 1 in pancreatic cancer |
| topic | pancreatic cancer cofilin-1 modeling molecular mechanism Boolean networks predicting therapeutic targets |
| url | https://www.mdpi.com/2072-6694/13/4/725 |
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