Inhibition of the LINE1-derived MET transcript induces apoptosis and oncoprotein knockdown in cancer cells
The expression of intragenic long interspersed nuclear elements 1 (LINE1s) can generate chimeric sequences disrupting host gene transcription. Among these, L1-MET, within mesenchymal epithelial transition (MET) oncogene, is particularly interesting, as its expression has been associated with the acq...
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Elsevier
2025-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253125000836 |
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| author | Umberto Miglio Enrico Berrino Daniele Avanzato Ivan Molineris Valentina Miano Melissa Milan Letizia Lanzetti Eugenio Morelli James M. Hughes Michele De Bortoli Anna Sapino Tiziana Venesio |
| author_facet | Umberto Miglio Enrico Berrino Daniele Avanzato Ivan Molineris Valentina Miano Melissa Milan Letizia Lanzetti Eugenio Morelli James M. Hughes Michele De Bortoli Anna Sapino Tiziana Venesio |
| author_sort | Umberto Miglio |
| collection | DOAJ |
| description | The expression of intragenic long interspersed nuclear elements 1 (LINE1s) can generate chimeric sequences disrupting host gene transcription. Among these, L1-MET, within mesenchymal epithelial transition (MET) oncogene, is particularly interesting, as its expression has been associated with the acquisition of tumorigenic phenotypes and cancer progression. We investigated the effects of targeting L1-MET in eight cancer cell lines derived from breast, lung, and gastrointestinal cancers, as well as in non-transformed human fibroblasts and lymphocytes, using specifically developed modified antisense oligonucleotides. Inhibition of L1-MET resulted in decreased cell viability, increased apoptosis, and gene expression profile reprogramming in cancer cells, including significant downregulation of MET and epidermal growth factor receptor (EGFR) proteins. These effects were related to the L1-MET/MET expression levels and the type of cellular addiction, with pronounced impacts in cells harboring MET gene amplification and EGFR-activating mutations. They were also detectable, though less pronounced, in cancer cells with steady-state levels of MET and EGFR proteins or addiction to other oncogenes. We demonstrate that targeting L1-MET can knockdown MET and EGFR protein. The restricted expression of L1-MET to cancer cells suggests that its inhibition could be an effective strategy to induce death in oncogene-addicted tumor cells and offers a potential means to overcome the limitations of conventional targeted therapies. |
| format | Article |
| id | doaj-art-30dce2bac9894d769b4e70b8b6c03931 |
| institution | OA Journals |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-30dce2bac9894d769b4e70b8b6c039312025-08-20T02:27:30ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-06-0136210252910.1016/j.omtn.2025.102529Inhibition of the LINE1-derived MET transcript induces apoptosis and oncoprotein knockdown in cancer cellsUmberto Miglio0Enrico Berrino1Daniele Avanzato2Ivan Molineris3Valentina Miano4Melissa Milan5Letizia Lanzetti6Eugenio Morelli7James M. Hughes8Michele De Bortoli9Anna Sapino10Tiziana Venesio11Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, ItalyCandiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy; Department of Medical Sciences, University of Torino, 10126 Torino, ItalyDepartment of Oncology, University of Torino Medical School, 10043 Orbassano, TO, ItalyDepartment of Life Sciences and System Biology and MBC, University of Torino, 10123 Torino, ItalyDepartment of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, TO, ItalyCandiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, ItalyCandiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy; Department of Oncology, University of Torino Medical School, 10043 Orbassano, TO, ItalyCandiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy; Department of Oncology, University of Torino Medical School, 10043 Orbassano, TO, ItalyCandiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, ItalyDepartment of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, TO, ItalyCandiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy; Department of Medical Sciences, University of Torino, 10126 Torino, ItalyCandiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy; Corresponding author: Tiziana Venesio, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy.The expression of intragenic long interspersed nuclear elements 1 (LINE1s) can generate chimeric sequences disrupting host gene transcription. Among these, L1-MET, within mesenchymal epithelial transition (MET) oncogene, is particularly interesting, as its expression has been associated with the acquisition of tumorigenic phenotypes and cancer progression. We investigated the effects of targeting L1-MET in eight cancer cell lines derived from breast, lung, and gastrointestinal cancers, as well as in non-transformed human fibroblasts and lymphocytes, using specifically developed modified antisense oligonucleotides. Inhibition of L1-MET resulted in decreased cell viability, increased apoptosis, and gene expression profile reprogramming in cancer cells, including significant downregulation of MET and epidermal growth factor receptor (EGFR) proteins. These effects were related to the L1-MET/MET expression levels and the type of cellular addiction, with pronounced impacts in cells harboring MET gene amplification and EGFR-activating mutations. They were also detectable, though less pronounced, in cancer cells with steady-state levels of MET and EGFR proteins or addiction to other oncogenes. We demonstrate that targeting L1-MET can knockdown MET and EGFR protein. The restricted expression of L1-MET to cancer cells suggests that its inhibition could be an effective strategy to induce death in oncogene-addicted tumor cells and offers a potential means to overcome the limitations of conventional targeted therapies.http://www.sciencedirect.com/science/article/pii/S2162253125000836MT: Oligonucleotides: Therapies and ApplicationsL1-METchimeric transcriptcancer cell deathMET protein knockdownintragenic-LINE1-derived transcript targeting |
| spellingShingle | Umberto Miglio Enrico Berrino Daniele Avanzato Ivan Molineris Valentina Miano Melissa Milan Letizia Lanzetti Eugenio Morelli James M. Hughes Michele De Bortoli Anna Sapino Tiziana Venesio Inhibition of the LINE1-derived MET transcript induces apoptosis and oncoprotein knockdown in cancer cells Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications L1-MET chimeric transcript cancer cell death MET protein knockdown intragenic-LINE1-derived transcript targeting |
| title | Inhibition of the LINE1-derived MET transcript induces apoptosis and oncoprotein knockdown in cancer cells |
| title_full | Inhibition of the LINE1-derived MET transcript induces apoptosis and oncoprotein knockdown in cancer cells |
| title_fullStr | Inhibition of the LINE1-derived MET transcript induces apoptosis and oncoprotein knockdown in cancer cells |
| title_full_unstemmed | Inhibition of the LINE1-derived MET transcript induces apoptosis and oncoprotein knockdown in cancer cells |
| title_short | Inhibition of the LINE1-derived MET transcript induces apoptosis and oncoprotein knockdown in cancer cells |
| title_sort | inhibition of the line1 derived met transcript induces apoptosis and oncoprotein knockdown in cancer cells |
| topic | MT: Oligonucleotides: Therapies and Applications L1-MET chimeric transcript cancer cell death MET protein knockdown intragenic-LINE1-derived transcript targeting |
| url | http://www.sciencedirect.com/science/article/pii/S2162253125000836 |
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