HSF1 is a prognostic determinant and therapeutic target in intrahepatic cholangiocarcinoma.

Autor: Cigliano A; Department of Medicine, Surgery, and Pharmacy, University of Sassari, via P. Manzella 4, Sassari, 07100, Italy.; Institute of Pathology, University of Regensburg, Regensburg, Germany., Gigante I; National Institute of Gastroenterology, IRCCS 'Saverio de Bellis', Castellana Grotte, Italy., Serra M; Institute of Pathology, University of Regensburg, Regensburg, Germany.; Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy., Vidili G; Department of Medicine, Surgery, and Pharmacy, University of Sassari, via P. Manzella 4, Sassari, 07100, Italy., Simile MM; Department of Medicine, Surgery, and Pharmacy, University of Sassari, via P. Manzella 4, Sassari, 07100, Italy., Steinmann S; Institute of Pathology, University of Regensburg, Regensburg, Germany., Urigo F; Institute of Pathology, University of Regensburg, Regensburg, Germany., Cossu E; Department of Medicine, Surgery, and Pharmacy, University of Sassari, via P. Manzella 4, Sassari, 07100, Italy., Pes GM; Department of Medicine, Surgery, and Pharmacy, University of Sassari, via P. Manzella 4, Sassari, 07100, Italy., Dore MP; Department of Medicine, Surgery, and Pharmacy, University of Sassari, via P. Manzella 4, Sassari, 07100, Italy., Ribback S; Institute of Pathology, University of Greifswald, Greifswald, Germany., Milia EP; Department of Medicine, Surgery, and Pharmacy, University of Sassari, via P. Manzella 4, Sassari, 07100, Italy., Pizzuto E; National Institute of Gastroenterology, IRCCS 'Saverio de Bellis', Castellana Grotte, Italy., Mancarella S; National Institute of Gastroenterology, IRCCS 'Saverio de Bellis', Castellana Grotte, Italy., Che L; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA., Pascale RM; Department of Medicine, Surgery, and Pharmacy, University of Sassari, via P. Manzella 4, Sassari, 07100, Italy., Giannelli G; National Institute of Gastroenterology, IRCCS 'Saverio de Bellis', Castellana Grotte, Italy., Evert M; Institute of Pathology, University of Regensburg, Regensburg, Germany., Chen X; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.; University of Hawaii Cancer Center, Honolulu, USA., Calvisi DF; Department of Medicine, Surgery, and Pharmacy, University of Sassari, via P. Manzella 4, Sassari, 07100, Italy. calvisid@uniss.it.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2024 Sep 06; Vol. 43 (1), pp. 253. Date of Electronic Publication: 2024 Sep 06.
DOI: 10.1186/s13046-024-03177-7
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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