期刊
NEOPLASIA
卷 23, 期 4, 页码 415-428出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neo.2021.03.006
关键词
Trop; Proteolytic processing; Signaling activation; Cell growth; Molecular modeling; Human cancer
类别
资金
- Fondazione of the Cassa di Risparmio della Provincia di Chieti
- Italian Association for Cancer Research (AIRC)
- ABO Foundation [VE01D0019, CH01D0081]
- Programma Per Giovani Ricercatori Rita Levi Montalcini, Italian Ministry of University and Research [PGR12I7N1Z]
Trop-2 undergoes cleavage induced by ADAM10, leading to cancer cell growth and metastatic spreading. The cleavage triggers a profound structural and functional rearrangement of Trop-2, highlighting the driving role of this activatory cleavage on malignant progression of tumors.
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 Trop2 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.
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