ArticleJournal of experimental & clinical cancer research : CR2022
Complexity of progranulin mechanisms of action in mesothelioma.
Article in Journal of experimental & clinical cancer research : CR, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 7 citations in OpenAlex.
- Functional characterization of FAM120A as a novel effector in the progranulin/EphA2 oncogenic axis in bladder cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- Analysis of metastasis‑related risk factors and clinical relevance in adult soft‑tissue sarcoma.Oncology letters · 2024Article
- Capsaicin Exerts Antitumor Activity in Mesothelioma Cells.Nutrients · 2024Article
- Article
- Review
- Orexins and Prostate Cancer: State of the Art and Potential Experimental and Therapeutic Perspectives.Cancer genomics & proteomics · 2023Review
- Progranulin and EGFR modulate receptor-like tyrosine kinase sorting and stability in mesothelioma cells.American journal of physiology. Cell physiology · 2023Article
- Progranulin Oncogenic Network in Solid Tumors.Cancers · 2023Review
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMesothelioma is an aggressive disease with limited therapeutic options. The growth factor progranulin plays a critical role in several cancer models, where it regulates tumor initiation and progression. Recent data from our laboratories have demonstrated that progranulin and its receptor, EphA2, constitute an oncogenic pathway in bladder cancer by promoting motility, invasion and in vivo tumor formation. Progranulin and EphA2 are expressed in mesothelioma cells but their mechanisms of action are not well defined. In addition, there are no data establishing whether the progranulin/EphA2 axis is tumorigenic for mesothelioma cells.
methodsThe expression of progranulin in various mesothelioma cell lines derived from all major mesothelioma subtypes was examined by western blots on cell lysates, conditioned media and ELISA assays. The biological roles of progranulin, EphA2, EGFR, RYK and FAK were assessed in vitro by immunoblots, human phospho-RTK antibody arrays, pharmacological (specific inhibitors) and genetic (siRNAs, shRNAs, CRISPR/Cas9) approaches, motility, invasion and adhesion assays. In vivo tumorigenesis was determined by xenograft models. Focal adhesion turnover was evaluated biochemically using focal adhesion assembly/disassembly assays and immunofluorescence analysis with focal adhesion-specific markers.
resultsIn the present study we show that progranulin is upregulated in various mesothelioma cell lines covering all mesothelioma subtypes and is an important regulator of motility, invasion, adhesion and in vivo tumor formation. However, our results indicate that EphA2 is not the major functional receptor for progranulin in mesothelioma cells, where progranulin activates a complex signaling network including EGFR and RYK. We further characterized progranulin mechanisms of action and demonstrated that progranulin, by modulating FAK activity, regulates the kinetic of focal adhesion disassembly, a critical step for cell motility.
conclusionCollectively, our results highlight the complexity of progranulin oncogenic signaling in mesothelioma, where progranulin modulate functional cross-talks between multiple RTKs, thereby suggesting the need for combinatorial therapeutic approaches to improve treatments of this aggressive disease.
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