Cigliano, Antonio and Gigante, Isabella and Serra, Marina and Vidili, Gianpaolo and Simile, Maria M. and Steinmann, Sara and Urigo, Francesco and Cossu, Eleonora and Pes, Giovanni M. and Dore, Maria P. and Ribback, Silvia and Milia, Egle P. and Pizzuto, Elena and Mancarella, Serena and Che, Li and Pascale, Rosa M. and Giannelli, Gianluigi and Evert, Matthias and Chen, Xin and Calvisi, Diego F. (2024) HSF1 is a prognostic determinant and therapeutic target in intrahepatic cholangiocarcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 43 (1): 253. ISSN , 1756-9966
Full text not available from this repository. (Request a copy)Abstract
BackgroundIntrahepatic 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.MethodsLevels 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.ResultsHuman 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.ConclusionsThe present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEAT-SHOCK FACTOR-1; NETWORK; CELLS; Intrahepatic cholangiocarcinoma; HSF1; Mouse models; KRIBB-11; Navitoclax |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Jan 2026 11:06 |
| Last Modified: | 16 Jan 2026 11:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65035 |
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