Glypican-3 (GPC3) inhibits metastasis development promoting dormancy in breast cancer cells by p38 MAPK pathway activation |
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| Institution: | 1. Universidad de Buenos Aires, Instituto de Oncología A.H. Roffo, Área Investigación, Buenos Aires, Argentina;2. CONICET;1. Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India;2. School of Biotechnology, University of Jammu, Jammu, 180006, India;3. Perelman School of Medicine, Cancer Biology Division, University of Pennsylvania, PA-19104, USA;4. Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India;5. Plant Biotechnology and System Biology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India;1. Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore 636921, Singapore;2. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskölds väg 20, Uppsala Se-751 85, Sweden;3. Institute of Radiochemistry and Radioecology, University of Pannonia, Egyetem u. 10, H-8200 Veszprém, Hungary;4. Department of Biophysics and Radiation Biology, Semmelweis University Faculty of Medicine, T?zoltó u. 37-47, Budapest H-1094, Hungary;1. Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran;2. Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran;3. Department of Medical Emergencies, School of Allied Medical Sciences, Bushehr University of Medical Sciences, Bushehr, Iran;4. Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran;5. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran;6. School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran;7. Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran;8. Cell Therapy and Regenerative Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran;1. Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Leninskiye Gory 1–73, Moscow, 119991, Russia;2. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskiye Gory 1–40, Moscow, 119991, Russia;3. Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, 119991, Russia;1. Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies of the National Polytechnic Institute, Av. IPN 2508, 07360 Mexico City, Mexico;2. Department of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute, Av. IPN 2508, 07360 Mexico City, Mexico |
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| Abstract: | GPC3 is a proteoglycan involved in the control of proliferation and survival, which has been linked to several tumor types. In this respect, we previously demonstrated that normal breast tissues exhibit high levels of GPC3, while its expression is diminished in tumors. However, the role of the GPC3 downregulation in breast cancer progression and its molecular and cellular operational machineries are not fully understood.In this study we showed that GPC3 reverts the epithelial-to-mesenchymal transition (EMT) underwent by mammary tumor cells, blocks metastatic spread and induces dormancy at secondary site. Using genetically modified murine breast cancer cell sublines, we demonstrated that the phospho-Erk/phospho-p38 ratio is lower in GPC3 reexpressing cells, while p21, p27 and SOX2 levels are higher, suggesting a dormant phenotype. In vivo metastasis assays confirmed that GPC3 reexpressing cells reduce their metastatic ability. Interestingly, the presence of dormant cells was evidenced in the lungs of inoculated mice. Dormant cells could reactivate their proliferative capacity, remain viable as well as tumorigenic, but they reentered in dormancy upon reaching secondary site. We also proved that GPC3 inhibits metastasis through p38 pathway activation. The in vivo inhibition of p38 induced an increase in cell invasion of GPC3 reexpressing orthotropic tumors as well as in spontaneous and experimental metastatic dissemination.In conclusion, our study shows that GPC3 returns mesenchymal-like breast cancer cells to an epithelial phenotype, impairs in vivo metastasis and induces tumor dormancy through p38 MAPK signaling activation. These results help to identify genetic determinants of dormancy and suggest the translational potential of research focusing in GPC3. |
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| Keywords: | Breast cancer Dormancy Epithelial-to-mesenchymal transition GPC3 Metastasis p38 MAPK |
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