Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis.

Autor:	Trerotola M; Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University 'G. D'Annunzio', Chieti, Italy; Department of Medical, Oral and Biotechnological Sciences, University 'G. d'Annunzio', Chieti, Italy., Guerra E; Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University 'G. D'Annunzio', Chieti, Italy; Department of Medical, Oral and Biotechnological Sciences, University 'G. d'Annunzio', Chieti, Italy., Ali Z; Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University 'G. D'Annunzio', Chieti, Italy., Aloisi AL; Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University 'G. D'Annunzio', Chieti, Italy., Ceci M; Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University 'G. D'Annunzio', Chieti, Italy., Simeone P; Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University 'G. D'Annunzio', Chieti, Italy., Acciarito A; Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University 'G. D'Annunzio', Chieti, Italy., Zanna P; Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University 'G. D'Annunzio', Chieti, Italy., Vacca G; Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University 'G. D'Annunzio', Chieti, Italy., D'Amore A; Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University 'G. D'Annunzio', Chieti, Italy., Boujnah K; Unit of Medical Genetics, Department of Biomedical Sciences (BIOMORF), University of Messina, Italy., Garbo V; Unit of Medical Genetics, Department of Biomedical Sciences (BIOMORF), University of Messina, Italy., Moschella A; Unit of Medical Genetics, Department of Biomedical Sciences (BIOMORF), University of Messina, Italy., Lattanzio R; Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University 'G. D'Annunzio', Chieti, Italy; Department of Medical, Oral and Biotechnological Sciences, University 'G. d'Annunzio', Chieti, Italy., Alberti S; Unit of Medical Genetics, Department of Biomedical Sciences (BIOMORF), University of Messina, Italy. Electronic address: salberti@unime.it.
Jazyk:	angličtina
Zdroj:	Neoplasia (New York, N.Y.) [Neoplasia] 2021 Apr; Vol. 23 (4), pp. 415-428. Date of Electronic Publication: 2021 Apr 08.
DOI:	10.1016/j.neo.2021.03.006
Abstrakt:	Trop-2 is a transmembrane signal transducer that can induce cancer growth. Using antibody targeting and N-terminal Edman degradation, we show here that Trop-2 undergoes cleavage in the first thyroglobulin domain loop of its extracellular region, between residues R87 and T88. Molecular modeling indicated that this cleavage induces a profound rearrangement of the Trop-2 structure, which suggested a deep impact on its biological function. No Trop-2 cleavage was detected in normal human tissues, whereas most tumors showed Trop-2 cleavage, including skin, ovary, colon, and breast cancers. Coimmunoprecipitation and mass spectrometry analysis revealed that ADAM10 physically interacts with Trop-2. Immunofluorescence/confocal time-lapse microscopy revealed that the two molecules broadly colocalize at the cell membrane. We show that ADAM10 inhibitors, siRNAs and shRNAs abolish the processing of Trop-2, which indicates that ADAM10 is an effector protease. Proteolysis of Trop-2 at R87-T88 triggered cancer cell growth both in vitro and in vivo. A corresponding role was shown for metastatic spreading of colon cancer, as the R87A-T88A Trop-2 mutant abolished xenotransplant metastatic dissemination. Activatory proteolysis of Trop-2 was recapitulated in primary human breast cancers. Together with the prognostic impact of Trop-2 and ADAM10 on cancers of the skin, ovary, colon, lung, and pancreas, these data indicate a driving role of this activatory cleavage of Trop-2 on malignant progression of tumors. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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