FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted

Vallejo, Adrián; Erice, Oihane; Entrialgo‐Cadierno, Rodrigo; Feliu, Iker; Guruceaga, Elizabeth; Perugorria, María J.; Olaizola, Paula; Muggli, Alexandra; Macaya, Irati; O’Dell, M.; Córdoba, Borja Ruiz-Fernández de; Ortiz‐Espinosa, Sergio; Hezel, Aram F.; Arozarena, Imanol; Lecanda, Fernando; Avila, Matı́as A.; Fernández‐Barrena, Maite G.; Evert, Matthias; Ponz-Sarvisé, Mariano; Calvisi, Diego F.; Bañales, Jesús M.; Vicent, Silvestre

doi:10.1016/j.jhep.2021.03.028

Cited by 35 publications

(23 citation statements)

References 79 publications

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“…Fra-1 as Prognostic Biomarker and Cancer Cell Addiction to Fra-1 Overexpression RNA expression profiling and IHC data show the prognostic relevance of Fra-1 and/or Fra-1-dependent transcriptomes. Time to recurrence and/or metastasis-free survival correlate with Fra-1 expression (alone or in multivariate analyses) in a wide range of adenocarcinomas, including breast [29,34,36,50,51], colon [30,35,41,48], lung [37], pancreas [37], cholangiocarcinoma [52], and squamous cell carcinomas, such as HNSCC (Head and Neck Squamous Cell Carcinoma) [53,54], ESCC (Esophageal Squamous Cell Carcinoma) [55,56], and OSCC (Oral Squamous Cell Carcinoma) [57]), along with non-epithelial cancers, such as glioma [58].…”

Section: Fra-1 In Tumor Growth Invasion and Metastasismentioning

confidence: 99%

The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting

Casalino

Talotta²,

Cimmino

et al. 2022

Cancers

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The genetic and epigenetic changes affecting transcription factors, coactivators, and chromatin modifiers are key determinants of the hallmarks of cancer. The acquired dependence on oncogenic transcriptional regulators, representing a major determinant of cancer cell vulnerability, points to transcription factors as ideal therapeutic targets. However, given the unavailability of catalytic activities or binding pockets for small-molecule inhibitors, transcription factors are generally regarded as undruggable proteins. Among components of the AP-1 complex, the FOS-family transcription factor Fra-1, encoded by FOSL1, has emerged as a prominent therapeutic target. Fra-1 is overexpressed in most solid tumors, in response to the BRAF-MAPK, Wnt-beta-catenin, Hippo-YAP, IL-6-Stat3, and other major oncogenic pathways. In vitro functional analyses, validated in onco-mouse models and corroborated by prognostic correlations, show that Fra-1-containing dimers control tumor growth and disease progression. Fra-1 participates in key mechanisms of cancer cell invasion, Epithelial-to-Mesenchymal Transition, and metastatic spreading, by driving the expression of EMT-inducing transcription factors, cytokines, and microRNAs. Here we survey various strategies aimed at inhibiting tumor growth, metastatic dissemination, and drug resistance by interfering with Fra-1 expression, stability, and transcriptional activity. We summarize several tools aimed at the design and tumor-specific delivery of Fra-1/AP-1-specific drugs. Along with RNA-based therapeutics targeting the FOSL1 gene, its mRNA, or cognate regulatory circRNAs, we will examine the exploitation of blocking peptides, small molecule inhibitors, and innovative Fra-1 protein degraders. We also consider the possible caveats concerning Fra-1 inhibition in specific therapeutic contexts. Finally, we discuss a recent suicide gene therapy-based approach, aimed at selectively killing the Fra-1-overexpressing neoplastic cells.

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Section: Fra-1 In Tumor Growth Invasion and Metastasismentioning

confidence: 99%

The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting

Casalino

Talotta²,

Cimmino

et al. 2022

Cancers

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“…Moreover, FOSL1 may play an important role in the development and metastasis of tumors (Maurus et al, 2017). It has been clearly reported that FOSL1 can also promote the progression of pancreatic cancer (Vallejo et al, 2017;Luo, He & Qiu, 2018), bile duct cancer (Vallejo et al, 2021), breast cancer (Kim et al, 2020Chen et al, 2018), bladder cancer (Cui et al, 2020;Gatta et al, 2019), stomach cancer (He et al, 2015) and esophageal cancer (Shen et al, 2020) through direct or indirect mechanisms. Therefore, high expression of FOSL1 may contribute to poor prognosis of LUAD from multiple aspects of tumor genesis and progression.…”

Section: Discussionmentioning

confidence: 99%

Signature identification of relapse-related overall survival of early lung adenocarcinoma after radical surgery

Han

Yue

Kong

et al. 2021

PeerJ

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Background The widespread use of low-dose chest CT screening has improved the detection of early lung adenocarcinoma. Radical surgery is the best treatment strategy for patients with early lung adenocarcinoma; however, some patients present with postoperative recurrence and poor prognosis. Through this study, we hope to establish a model that can identify patients that are prone to recurrence and have poor prognosis after surgery for early lung adenocarcinoma. Materials and Methods We screened prognostic and relapse-related genes using The Cancer Genome Atlas (TCGA) database and the GSE50081 dataset from the Gene Expression Omnibus (GEO) database. The GSE30219 dataset was used to further screen target genes and construct a risk prognosis signature. Time-dependent ROC analysis, calibration degree analysis, and DCA were used to evaluate the reliability of the model. We validated the TCGA dataset, GSE50081, and GSE30219 internally. External validation was conducted in the GSE31210 dataset. Results A novel four-gene signature (INPP5B, FOSL2, CDCA3, RASAL2) was established to predict relapse-related survival outcomes in patients with early lung adenocarcinoma after surgery. The discovery of these genes may reveal the molecular mechanism of recurrence and poor prognosis of early lung adenocarcinoma. In addition, ROC analysis, calibration analysis and DCA were used to verify the genetic signature internally and externally. Our results showed that our gene signature had a good predictive ability for recurrence and prognosis. Conclusions We established a four-gene signature and predictive model to predict the recurrence and corresponding survival rates in patients with early lung adenocarcinoma after surgery. These may be helpful for reforumulating post-operative consolidation treatment strategies.

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“…Numerous studies have confirmed that Fra-1 is crucially involved in human tumor progression and metastasis, thus representing a promising therapeutic target ( 178 , 179 ). As we all know, inflammation and cancer is intimately linked, the tumor microenvironment (TME) plays a prominent role in the growth of tumor cells.…”

Section: Immune-related Diseasesmentioning

confidence: 99%

“…Another strategy for targeting Fra-1 is genetic inhibition. Vicent’s group reported that deficiency for Fra-1 in a genetically engineered mouse model of Cholangiocarcinoma using constitutive and inducible short-hairpin RNAs extended mouse survival by decreasing the oncogenic potential of transformed cholangiocytes ( 179 ).…”

Section: Fra-1 Related Treatmentmentioning

confidence: 99%

“…For example, the expression of the Mevalonate pathway gene HMGCS1 is controlled by direct FOSL1 promoter binding. Genetic and pharmacological inhibition of HMGCS1 and AURKA leads to loss of FOSL1, which can reduce the carcinogenic potential of transformed bile duct cells and prolong mouse survival ( 179 ). As previously mentioned, MAP kinase pathway plays a role in the content and stability of Fra-1 in cells.…”

Section: Fra-1 Related Treatmentmentioning

confidence: 99%

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The Fra-1: Novel role in regulating extensive immune cell states and affecting inflammatory diseases

Zhou

Chen

et al. 2022

Front. Immunol.

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Fra-1(Fos-related antigen1), a member of transcription factor activator protein (AP-1), plays an important role in cell proliferation, apoptosis, differentiation, inflammation, oncogenesis and tumor metastasis. Accumulating evidence suggest that the malignancy and invasive ability of tumors can be significantly changed by directly targeting Fra-1. Besides, the effects of Fra-1 are gradually revealed in immune and inflammatory settings, such as arthritis, pneumonia, psoriasis and cardiovascular disease. These regulatory mechanisms that orchestrate immune and non-immune cells underlie Fra-1 as a potential therapeutic target for a variety of human diseases. In this review, we focus on the current knowledge of Fra-1 in immune system, highlighting its unique importance in regulating tissue homeostasis. In addition, we also discuss the possible critical intervention strategy in diseases, which also outline future research and development avenues.

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FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted

Cited by 35 publications

References 79 publications

The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting

The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting

Signature identification of relapse-related overall survival of early lung adenocarcinoma after radical surgery

The Fra-1: Novel role in regulating extensive immune cell states and affecting inflammatory diseases

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