ASPH-notch Axis guided Exosomal delivery of Prometastatic Secretome renders breast Cancer multi-organ metastasis
| العنوان: | ASPH-notch Axis guided Exosomal delivery of Prometastatic Secretome renders breast Cancer multi-organ metastasis |
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| المؤلفون: | Lianxin Liu, Qiushi Lin, Bei Sun, Xianglu Kong, Fanzheng Meng, Min Li, Fuliang He, Jack R. Wands, Ziran Zhang, Qinggang Xu, Xuesong Chen, Xuewei Bai, Kosuke Ogawa, Mien Chie Hung, Ruipeng Song, Xiaoqun Dong, Shugeng Zhang |
| المصدر: | Molecular Cancer, Vol 18, Iss 1, Pp 1-17 (2019) Molecular Cancer |
| بيانات النشر: | BMC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Proteome, Angiogenesis, Muscle Proteins, Cell Communication, medicine.disease_cause, Exosomes, Ligands, Metastasis, Mixed Function Oxygenases, Mice, 0302 clinical medicine, Breast cancer, Genes, Reporter, Neoplasm Metastasis, Tube formation, biology, Receptors, Notch, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunohistochemistry, Extracellular Matrix, Cell Transformation, Neoplastic, Phenotype, Oncology, 030220 oncology & carcinogenesis, Molecular Medicine, Heterografts, Female, Signal Transduction, Notch, Aspartate β-hydroxylase (ASPH), Notch signaling pathway, Breast Neoplasms, Exosome, Models, Biological, lcsh:RC254-282, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Research, Calcium-Binding Proteins, Intravasation, Membrane Proteins, medicine.disease, Matrix Metalloproteinases, ASPH, Disease Models, Animal, 030104 developmental biology, Cancer research, biology.protein, Carcinogenesis, Biomarkers |
| الوصف: | Background Aspartate β-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer. Methods Stable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied. Results Through physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH’s β-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis. Conclusions ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH’s pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy. |
| اللغة: | English |
| تدمد: | 1476-4598 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::013ddc4c7d77d79defa1f1438bca2a90Test http://link.springer.com/article/10.1186/s12943-019-1077-0Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....013ddc4c7d77d79defa1f1438bca2a90 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14764598 |
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