title: Neutrophil elastase-dependent cleavage compromises the tumor suppressor role of EMILIN1.
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.
authors: Experimental Oncology 2, CRO, IRCCS, National Cancer Institute, Aviano, PN, Italy.
authors: Eliana
authors: E
authors: Pivetta
authors: Experimental Oncology 2, CRO, IRCCS, National Cancer Institute, Aviano, PN, Italy.
authors: Carla
authors: C
authors: Danussi
authors: Experimental Oncology 2, CRO, IRCCS, National Cancer Institute, Aviano, PN, Italy.
authors: Bruna
authors: B
authors: Wassermann
authors: Experimental Oncology 2, CRO, IRCCS, National Cancer Institute, Aviano, PN, Italy.
authors: Teresa Maria Elisa
authors: TM
authors: Modica
authors: Experimental Oncology 2, CRO, IRCCS, National Cancer Institute, Aviano, PN, Italy.
authors: Lisa
authors: L
authors: Del Bel Belluz
authors: Division of Pathology, CRO, IRCCS, National Cancer Institute, Aviano, PN, Italy.
authors: Vincenzo
authors: V
authors: Canzonieri
authors: Experimental Oncology 2, CRO, IRCCS, National Cancer Institute, Aviano, PN, Italy; Department of Medical and Biomedical Sciences, University of Udine, Italy; MATI (Microgravity, Ageing, Training, Immobility) Excellence Center, University of Udine, Italy.
authors: Alfonso
authors: A
authors: Colombatti
authors: Experimental Oncology 2, CRO, IRCCS, National Cancer Institute, Aviano, PN, Italy. Electronic address: pspessotto@cro.it.
authors: Paola
authors: P
authors: Spessotto
mesh_terms: D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D039001:Integrin alpha Chains / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology; D059748:Proteolysis; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D039001:Integrin alpha Chains; D016023:Integrins; D008562:Membrane Glycoproteins; C030340:elastin microfibril interface located protein; C113256:integrin alpha 9 beta 1; C084613:integrin alpha9; D019272:Leukocyte Elastase
keywords: Cleavage; EMILIN1; Extracellular matrix; Neutrophil elastase; Proliferation