MMP-3 cleavage of Lamin A induces pro-migratory nuclear deformity, nucleophagy, and their autophagic secretion with extracellular vesicles in metastatic cancer
Rattachement africain : jp, Égypte, in, cn, us. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that cleave a plethora of substrates, including components of the extracellular matrix and cell-surface-associated proteins, as well as intracellular targets. MMPs have also been found in extracellular vesicles (EVs), such as exosomes. MMP-3 promotes tumor growth, epithelial-to-mesenchymal transition, genome instability, migration, invasion, and metastasis of cancer cells, and nuclear MMP-3 controls gene transcription. Intranuclear proteolysis by MMPs may significantly alter cancer progression. However, the nuclear substrates of MMP-3 have not been well investigated. In this study, we performed proteomic analyses to identify the nuclear substrates and EV proteins regulated by MMP-3. While rabidly metastatic colon cancer (LuM1) three-dimensionally cultured tumoroids secreted EVs containing 30 protein types, including Lamin A (LMNA), MMP-3, fibronectin (FN1), HSPA8 (Hsc70), β-actin (ACTB), and vimentin (VIM), CRISPR/Cas9-based knockout of MMP-3 reduced the secretion of these proteins in EVs. Notably, EV-bound cleaved Lamin secretion was confirmed by immunoelectron microscopy. Also, MMP-3 formed proteolytic dimers via its hemopexin-like repeat domains in nuclei. Many nuclear MMP-3-binding proteins, including Lamin A/C, histones, topoisomerases, and hnRNPs, were screened by co-immunoprecipitation followed by proteomics. Proteolytic MMP-3 overexpression generated a C-terminal 30-kDa fragment of Lamin A, whose cleavage site was defined via structural analysis. MMP-3 digestion of Lamin A induced nuclear deformity (atypia) required for cell migration in confined space. The cleaved Lamin A and MMP-3 were transported with autophagosomes (LC3B+), nucleophagosomes, and amphisomes (CD63 + LC3B+) and co-secreted with EVs. Proteolytic MMP-3 also induced nuclear speckles of Lamin A, suggesting their roles in transcription and splicing. Clinical analysis revealed that high expressions of MMP3 and LMNA were significantly seen in head and neck squamous cell carcinoma (HNSC) than in the other 16 cancer types, and predicted poor prognosis of patients suffering from HNSC, pancreatic, rectum and lung adenocarcinomas at specific stages. Immunohistochemistry revealed that nuclear MMP-3 and cleaved Lamin were significantly higher expressed in stage IV metastatic HNSC cases than in stage I non-metastatic cases. Taken together, MMP3-cleavage of Lamin A induces nuclear deformity, nucleophagy, and their autophagic co-secretion with EVs in metastatic cancer. Also, high expression of MMP-3 and secretion of Lamin A can predict poor prognosis in multiple cancer types at specific stages.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- MMP-3 cleavage of Lamin A induces pro-migratory nuclear deformity, nucleophagy, and their autophagic secretion with extracellular vesicles in metastatic cancer
- Date Crossref
- 15/01/2026
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Okayama University Research practicum program pays non établi dans la noticeUniversité ou école supérieure
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Ain Shams University Égypte (code pays fourni par la source)Université ou école supérieure
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Indian Institute of Toxicology Research pays non établi dans la noticeStructure de recherche
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Okayama University Hospital pays non établi dans la noticeÉtablissement de santé
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Harbin Medical University Department of Clinical Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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Third Affiliated Hospital of Harbin Medical University pays non établi dans la noticeÉtablissement de santé
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Hiroshima Institute of Technology pays non établi dans la noticeUniversité ou école supérieure
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Beth Israel Deaconess Medical Center Department of Radiation Oncology pays non établi dans la noticeÉtablissement de santé
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Faculty of Medicine Department of Dental Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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Faculty of Science Department of Biochemistry Cairo, Égypte (pays nommé en fin d’affiliation)Université ou école supérieure
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Council of Scientific & Industrial Research-Indian Institute of Toxicological Research pays non établi dans la noticeStructure de recherche
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Faculty of Environmental Studies Department of Food and Health Sciences pays non établi dans la noticeUniversité ou école supérieure
Research practicum program — Okayama University, Ain Shams University (Égypte) et Indian Institute of Toxicology Research, avec 9 autres affiliations. Pays d’affiliation : Égypte.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.