FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted

JOURNAL OF HEPATOLOGY

卷:75

Article

Vallejo, Adrian¹  Erice, Oihane^1,2  Entrialgo-Cadierno, Rodrigo¹  Feliu, Iker¹  Guruceaga, Elizabeth^2,3,4  Perugorria, Maria J.^5,6,7  Olaizola, Paula⁶  Muggli, Alexandra⁸  Macaya, Irati¹  O'Dell, Michael⁹  Ruiz-Fernandez De Cordoba, Borja¹  Ortiz-Espinosa, Sergio¹  Hezel, Aram F.⁹  Arozarena, Imanol^2,10  Lecanda, Fernando^1,2,11,12  Avila, Matias A.^2,7,13  Fernandez-Barrena, Maite G.^2,7,13  Evert, Matthias⁸  Ponz-Sarvise, Mariano¹⁴  Calvisi, Diego F.⁸  Banales, Jesus M.^6,7,15  Vicent, Silve^1,2,11,12 

[1] Univ Navarra, Ctr Appl Med Res, Program Solid Tumours, Pamplona, Spain

[2] Navarra Inst Hlth Res, IdiSNA, Pamplona, Spain

[3] Univ Navarra, Ctr Appl Med Res, Computat Biol Program, Pamplona, Spain

[4] ProteoRed Inst Salud Carlos III ISCIII, Madrid, Spain

[5] Univ Basque Country, San Sebastian, Spain

[6] Univ Basque Country, Dept Liver & Gastrointestinal Dis, Biodonostia Hlth Res Inst, Donostia Univ Hosp,UPV EHU, San Sebastian, Spain

[7] Inst Salud Carlos III, Natl Inst Study Liver & Gastrointestinal Dis, CIBERehd, Madrid, Spain

[8] Univ Regensburg, Inst Pathol, Regensburg, Germany

[9] Univ Rochester, Med Ctr, Rochester, NY 14642 USA

[10] Univ Publ Navarra UPNA, Complejo Hosp Navarra CHN, Canc Signalling Unit, Navarrabiomed, Pamplona, Spain

[11] Inst Salud Carlos III, Ctr Invest Biomed Red Canc, CIBERONC, Madrid, Spain

[12] Univ Navarra, Dept Pathol Anat & Physiol, Pamplona, Spain

[13] Univ Navarra, Ctr Appl Med Res, Hepatol Program, Pamplona, Spain

[14] Clin Univ Navarra, Dept Med Oncol, Pamplona, Spain

[15] Ikerbasque, Basque Fdn Sci, Bilbao, Spain

关键词: FOSL1;    cholangiocarcinoma;    transcription factors;    genetics;    targeted therapies;   

DOI  :  10.1016/j.jhep.2021.03.028

来源: Elsevier

【 摘 要 】

Background & Aims: Cholangiocarcinoma (CCA) is a neoplasia of the biliary tract driven by genetic, epigenetic and transcriptional mechanisms. Herein, we investigated the role of the transcription factor FOSL1, as well as its downstream transcriptional effectors, in the development and progression of CCA. Methods: FOSL1 was investigated in human CCA clinical samples. Genetic inhibition of FOSL1 in human and mouse CCA cell lines was performed in in vitro and in vivo models using constitutive and inducible short-hairpin RNAs. Conditional FOSL1 ablation was done using a genetically engineered mouse (GEM) model of CCA (mutant KRAS and Trp53 knockout). Followup RNA and chromatin immunoprecipitation (ChIP) sequencing analyses were carried out and downstream targets were validated using genetic and pharmacological inhibition. Results: An inter-species analysis of FOSL1 in CCA was conducted. First, FOSL1 was found to be highly upregulated in human and mouse CCA, and associated with poor patient survival. Pharmacological inhibition of different signalling pathways in CCA cells converged on the regulation of FOSL1 expression. Functional experiments showed that FOSL1 is required for cell proliferation and cell cycle progression in vitro, and for tumour growth and tumour maintenance in both orthotopic and subcutaneous xenograft models. Likewise, FOSL1 genetic abrogation in a GEM model of CCA extended mouse survival by decreasing the oncogenic potential of transformed cholangiocytes. RNA and ChIP sequencing studies identified direct and indirect transcriptional effectors such as HMGCS1 and AURKA, whose genetic and pharmacological inhibition phenocopied FOSL1 loss. Conclusions: Our data illustrate the functional and clinical relevance of FOSL1 in CCA and unveil potential targets amenable to pharmacological inhibition that could enable the implementation of novel therapeutic strategies. Lay summary: Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

【 授权许可】

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