HSF1 is a prognostic determinant and therapeutic target in intrahepatic cholangiocarcinoma
Gespeichert in:
| Titel: | HSF1 is a prognostic determinant and therapeutic target in intrahepatic cholangiocarcinoma |
|---|---|
| Autoren: | Cigliano, Antonio, Gigante, Isabella, Serra, Marina, Vidili, Gianpaolo, Simile, Maria M., Steinmann, Sara, Urigo, Francesco, Cossu, Eleonora, Pes, Giovanni M., Dore, Maria P., Ribback, Silvia, Milia, Egle P., Pizzuto, Elena, Mancarella, Serena, Che, Li, Pascale, Rosa M., Giannelli, Gianluigi, Evert, Matthias, Chen, Xin, Calvisi, Diego F. |
| Quelle: | J Exp Clin Cancer Res Journal of Experimental & Clinical Cancer Research, Vol 43, Iss 1, Pp 1-17 (2024) |
| Verlagsinformationen: | Springer Science and Business Media LLC, 2024. |
| Publikationsjahr: | 2024 |
| Schlagwörter: | Heat Shock Transcription Factors/metabolism [MeSH], Cell Line, Tumor [MeSH], Cell Proliferation [MeSH], Heat Shock Transcription Factors/genetics [MeSH], Humans [MeSH], Bile Duct Neoplasms/metabolism [MeSH], Cholangiocarcinoma/drug therapy [MeSH], Bile Duct Neoplasms/pathology [MeSH], Mouse models, Animals [MeSH], Intrahepatic cholangiocarcinoma, Cholangiocarcinoma/metabolism [MeSH], Mice [MeSH], Cholangiocarcinoma/pathology [MeSH], Research, Navitoclax, Prognosis [MeSH], Bile Duct Neoplasms/drug therapy [MeSH], HSF1, Cholangiocarcinoma/genetics [MeSH], KRIBB-11, Disease Models, Animal [MeSH], Bile Duct Neoplasms/genetics [MeSH], Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, Cholangiocarcinoma, Mice, Disease Models, Animal, Heat Shock Transcription Factors, Bile Duct Neoplasms, Cell Line, Tumor, Humans, Animals, RC254-282, Cell Proliferation |
| Beschreibung: | Background Intrahepatic cholangiocarcinoma (iCCA) is a lethal primary liver tumor characterized by clinical aggressiveness, poor prognosis, and scarce therapeutic possibilities. Therefore, new treatments are urgently needed to render this disease curable. Since cumulating evidence supports the oncogenic properties of the Heat Shock Factor 1 (HSF1) transcription factor in various cancer types, we investigated its pathogenetic and therapeutic relevance in iCCA. Methods Levels of HSF1 were evaluated in a vast collection of iCCA specimens. The effects of HSF1 inactivation on iCCA development in vivo were investigated using three established oncogene-driven iCCA mouse models. In addition, the impact of HSF1 suppression on tumor cells and tumor stroma was assessed in iCCA cell lines, human iCCA cancer-associated fibroblasts (hCAFs), and patient-derived organoids. Results Human preinvasive, invasive, and metastatic iCCAs displayed widespread HSF1 upregulation, which was associated with a dismal prognosis of the patients. In addition, hydrodynamic injection of a dominant-negative form of HSF1 (HSF1dn), which suppresses HSF1 activity, significantly delayed cholangiocarcinogenesis in AKT/NICD, AKT/YAP, and AKT/TAZ mice. In iCCA cell lines, iCCA hCAFs, and patient-derived organoids, administration of the HSF1 inhibitor KRIBB-11 significantly reduced proliferation and induced apoptosis. Cell death was profoundly augmented by concomitant administration of the Bcl-xL/Bcl2/Bcl-w inhibitor ABT-263. Furthermore, KRIBB-11 reduced mitochondrial bioenergetics and glycolysis of iCCA cells. Conclusions The present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis. |
| Publikationsart: | Article Other literature type |
| Dateibeschreibung: | application/pdf |
| Sprache: | English |
| ISSN: | 1756-9966 |
| DOI: | 10.1186/s13046-024-03177-7 |
| Zugangs-URL: | https://pubmed.ncbi.nlm.nih.gov/39243039 https://doaj.org/article/4358a36380b8455e977ec4053d406fe2 https://repository.publisso.de/resource/frl:6508490 |
| Rights: | CC BY URL: http://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (http://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
| Dokumentencode: | edsair.doi.dedup.....2bc535e34a0b0a4cb7c361bea3412834 |
| Datenbank: | OpenAIRE |
Full Text 
Full Text Finder 
Nájsť tento článok vo Web of Science | Abstract: | Background Intrahepatic cholangiocarcinoma (iCCA) is a lethal primary liver tumor characterized by clinical aggressiveness, poor prognosis, and scarce therapeutic possibilities. Therefore, new treatments are urgently needed to render this disease curable. Since cumulating evidence supports the oncogenic properties of the Heat Shock Factor 1 (HSF1) transcription factor in various cancer types, we investigated its pathogenetic and therapeutic relevance in iCCA. Methods Levels of HSF1 were evaluated in a vast collection of iCCA specimens. The effects of HSF1 inactivation on iCCA development in vivo were investigated using three established oncogene-driven iCCA mouse models. In addition, the impact of HSF1 suppression on tumor cells and tumor stroma was assessed in iCCA cell lines, human iCCA cancer-associated fibroblasts (hCAFs), and patient-derived organoids. Results Human preinvasive, invasive, and metastatic iCCAs displayed widespread HSF1 upregulation, which was associated with a dismal prognosis of the patients. In addition, hydrodynamic injection of a dominant-negative form of HSF1 (HSF1dn), which suppresses HSF1 activity, significantly delayed cholangiocarcinogenesis in AKT/NICD, AKT/YAP, and AKT/TAZ mice. In iCCA cell lines, iCCA hCAFs, and patient-derived organoids, administration of the HSF1 inhibitor KRIBB-11 significantly reduced proliferation and induced apoptosis. Cell death was profoundly augmented by concomitant administration of the Bcl-xL/Bcl2/Bcl-w inhibitor ABT-263. Furthermore, KRIBB-11 reduced mitochondrial bioenergetics and glycolysis of iCCA cells. Conclusions The present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis. |
|---|---|
| ISSN: | 17569966 |
| DOI: | 10.1186/s13046-024-03177-7 |