Neutrophil elastase-dependent cleavage compromises the tumor suppressor role of EMILIN1 |
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| Affiliation: | 1. Experimental Oncology 2, CRO, IRCCS, National Cancer Institute, Aviano, PN, Italy;2. Division of Pathology, CRO, IRCCS, National Cancer Institute, Aviano, PN, Italy;3. Department of Medical and Biomedical Sciences, University of Udine, Italy;4. MATI (Microgravity, Ageing, Training, Immobility) Excellence Center, University of Udine, Italy;11. Gastroenterology Operative Unit, Azienda Ospedaliera San Camillo-Forlanini FR, Rome, Italy;22. Gastroenterology and Digestive Endoscopy, Nuovo Regina Margherita Hospital, Rome, Italy;33. Gastroenterology and Digestive Endoscopy, Academic Hospital Cattinara, Trieste, Italy;44. Department of Internal Medicine ASST Lecco, Lecco, Italy;55. Gastroenterology Unit, AULSS 3 Serenissima, Venice, Italy;66. Gastrointestinal Endoscopy Unit, Ospedale SS Cosma e Damiano, Pescia, Italy;77. Gastroenterology Unit, S. Maria delle Croci Hospital, Ravenna, Italy;88. Gastrointestinal Unit, G. Brotzu Hospital, Cagliari, Italy;99. Department of Medicine, Vittorio Emanuele III Hospital, Salemi, Trapani, Italy;1. Gastroenterology Operative Unit, Azienda Ospedaliera San Camillo-Forlanini FR, Rome, Italy;2. Gastroenterology and Digestive Endoscopy, Nuovo Regina Margherita Hospital, Rome, Italy;3. Gastroenterology and Digestive Endoscopy, Academic Hospital Cattinara, Trieste, Italy;4. Department of Internal Medicine ASST Lecco, Lecco, Italy;5. Department of Oncological Gastroenterology, S.O.C. Gastroenterologia Oncologica Sperimentale, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, PN, Italy;6. Department of Medicine, Vittorio Emanuele III Hospital, Salemi, Trapani, Italy;1. Unit of Oncological Gastroenterology, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini, 2, Aviano 33081, Italy;2. Unit of Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy;3. Department of Medicine (DAME), University of Udine, Udine, Italy |
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| Abstract: | Proteolysis of the extracellular matrix (ECM) is a key event in tumor growth and progression. The breakdown of ECM can lead to the generation of bioactive fragments that promote cell growth and spread. EMILIN1, a multidomain glycoprotein expressed in several tissues, exerts a crucial regulatory function through the engagement of α4/α9 integrins. Unlike the majority of ECM molecules that elicit a proliferative program, the signals emitting from EMILIN1 engaged by α4/α9β1 integrins are antiproliferative. In this study, aimed to demonstrate if the suppressor role of EMILIN1 was related to its structural integrity, we tested the possibility that EMILIN1 could be specifically cleaved. Among the proteolytic enzymes released in the tumor microenvironment we showed that neutrophil elastase cleaved EMILIN1 in three/four major fragments. The consequence of this proteolytic process was the impairment of its anti-proliferative role. Accordingly, EMILIN1 was digested in sarcomas and ovarian cancers. Sarcoma specimens were infiltrated by neutrophils (PMNs) and stained positively for elastase. The present findings highlight the peculiar activity of PMN elastase in disabling EMILIN1 suppressor function. |
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