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

IF 11.4 1区医学 Q1 ONCOLOGY

Journal of Experimental & Clinical Cancer Research Pub Date : 2024-09-06 DOI:10.1186/s13046-024-03177-7

Antonio Cigliano, Isabella Gigante, Marina Serra, Gianpaolo Vidili, Maria M Simile, Sara Steinmann, Francesco Urigo, Eleonora Cossu, Giovanni M Pes, Maria P Dore, Silvia Ribback, Egle P Milia, Elena Pizzuto, Serena Mancarella, Li Che, Rosa M Pascale, Gianluigi Giannelli, Matthias Evert, Xin Chen, Diego F Calvisi

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引用次数: 0

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.

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HSF1 是肝内胆管癌的预后决定因素和治疗靶点。

背景：肝内胆管癌（iCCA）是一种致命的原发性肝肿瘤，其特点是临床侵袭性强、预后差、治疗手段少。因此，迫切需要新的治疗方法来治愈这种疾病。由于越来越多的证据支持热休克因子 1（HSF1）转录因子在各种癌症类型中的致癌特性，我们研究了它在 iCCA 中的致病性和治疗相关性：方法：在大量 iCCA 标本中评估 HSF1 的水平。方法：在大量 iCCA 标本中评估了 HSF1 的水平，并使用三种已建立的癌基因驱动 iCCA 小鼠模型研究了 HSF1 失活对 iCCA 体内发展的影响。此外，还评估了抑制 HSF1 对 iCCA 细胞系、人 iCCA 癌相关成纤维细胞（hCAFs）和源自患者的器官组织的肿瘤细胞和肿瘤基质的影响：结果：人类浸润前、浸润性和转移性iCCA显示出广泛的HSF1上调，这与患者的不良预后有关。此外，在 AKT/NICD、AKT/YAP 和 AKT/TAZ 小鼠体内注射抑制 HSF1 活性的显性阴性 HSF1（HSF1dn）能显著延缓胆管癌的发生。在 iCCA 细胞系、iCCA hCAFs 和患者衍生的器官组织中，服用 HSF1 抑制剂 KRIBB-11 能明显减少细胞增殖并诱导细胞凋亡。同时使用Bcl-xL/Bcl2/Bcl-w抑制剂ABT-263可大大增加细胞死亡。此外，KRIBB-11还降低了iCCA细胞的线粒体生物能和糖酵解：本研究数据强调了 HSF1 在胆管癌发生过程中的重要致病、预后和治疗作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Experimental & Clinical Cancer Research 医学-肿瘤学

CiteScore

18.20

自引率

1.80%

发文量

333

审稿时长

1 months

期刊介绍： The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.