Progranulin/EphA2 axis: A novel oncogenic mechanism in bladder cancer
| Autor: | Andrea Morrione, Renato V. Iozzo, Antonino Belfiore, Simone Buraschi, Chiara Palladino, Shi-Qiong Xu, Thomas Neill |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Liprinα-1 Progranulin Epithelial-Mesenchymal Transition Cell Survival medicine.medical_treatment Motility Biology EphA2 medicine.disease_cause Article 03 medical and health sciences Gene Knockout Techniques 0302 clinical medicine Progranulins Cell Movement Cell Line Tumor mental disorders medicine Humans Phosphorylation Receptor Molecular Biology Protein kinase B Cell Proliferation Bladder cancer Growth factor Receptor EphA2 EPH receptor A2 medicine.disease Actin cytoskeleton Up-Regulation Gene Expression Regulation Neoplastic 030104 developmental biology Urinary Bladder Neoplasms 030220 oncology & carcinogenesis Cancer research Female Cisplatin Carcinogenesis |
| Zdroj: | Matrix Biol |
| ISSN: | 1569-1802 |
| Popis: | The growth factor progranulin plays a critical role in bladder cancer by modulating tumor cell motility and invasion. Progranulin regulates remodeling of the actin cytoskeleton by interacting with drebrin, an actin binding protein that regulates tumor growth. We previously discovered that progranulin depletion inhibits epithelial-to-mesenchymal transition and markedly reduces in vivo tumor growth. Moreover, progranulin depletion sensitizes urothelial cancer cells to cisplatin treatment, further substantiating a pro-survival function of progranulin. Until recently, the progranulin signaling receptor remained unidentified, precluding a full understanding of progranulin action in tumor cell biology. We recently identified EphA2, a member of a large family of receptor tyrosine-kinases, as the functional receptor for progranulin. However, it is not established whether EphA2 plays an oncogenic role in bladder cancer. Here we demonstrate that progranulin, and not ephrin-A1, the canonical ligand for EphA2, is the predominant EphA2 ligand in bladder cancer. Progranulin evoked Akt- and Erk1/2-mediated EphA2 phosphorylation at Ser897, which could drive bladder tumorigenesis. We discovered that EphA2 depletion severely blunted progranulin-dependent motility and anchorage-independent growth, and sensitized bladder cancer cells to cisplatin treatment. We further defined the mechanisms of progranulin/EphA2-dependent motility by identifying liprin-α1 as a novel progranulin-dependent EphA2 interacting protein and establishing its critical role in cell motility. The discovery of EphA2 as the functional signaling receptor for progranulin and the identification of novel downstream effectors offer a new avenue for understanding the underlying mechanism of progranulin action and may constitute novel clinical and therapeutic targets in bladder cancer. |
| Databáze: | OpenAIRE |
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