Journal article
Inhibition of kras-derived exosomes downregulates immunosuppressive BACH2/GATA-3 expression via RIP-3 dependent necroptosis and miR-146/miR-210 modulation.
- Petanidis S Department of Medicine, Laboratory of Medical Biology and Genetics, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece; Department of Pulmonology, I.M. Sechenov First Moscow State Medical University, Moscow, 119992, Russian Federation.
- Domvri K Pulmonary Department-Oncology Unit, "G. Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, 57010, Greece.
- Porpodis K Pulmonary Department-Oncology Unit, "G. Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, 57010, Greece.
- Anestakis D Department of Medicine, Laboratory of Forensic Medicine and Toxicology, Aristotle University of Thessaloniki, 54124, Greece.
- Freitag L Department of Pulmonology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich Switzerland.
- Hohenforst-Schmidt W Medical Clinic I, "Fuerth" Hospital, University of Erlangen, 91054, Fuerth, Germany.
- Tsavlis D Department of Medicine, Laboratory of Experimental Physiology, Aristotle University of Thessaloniki, 54124, Greece.
- Zarogoulidis K Department of Medicine, Laboratory of Medical Biology and Genetics, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece. Electronic address: zarog@med.auth.gr.
- 2020-01-10
Published in:
- Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. - 2020
BACH2
Exosomes
Kras
Necroptosis
miR-146/miR-210
Aniline Compounds
Animals
Basic-Leucine Zipper Transcription Factors
Benzylidene Compounds
Carboplatin
Carrier Proteins
Chromatin Assembly and Disassembly
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
Exosomes
GATA3 Transcription Factor
Humans
Immunosuppression
Lung Neoplasms
Membrane Proteins
Mice
Mice, Nude
MicroRNAs
Models, Animal
Necroptosis
Neoplasm Metastasis
Nuclear Receptor Co-Repressor 1
Proto-Oncogene Proteins p21(ras)
Receptor-Interacting Protein Serine-Threonine Kinases
Thyroid Hormones
Tumor Microenvironment
English
Immunosuppressive chemoresistance is a major challenge in lung cancer treatment. Exosomes present in the tumor microenviroment are implicated in chemoresistant-related immune suppression, and metastasis but the exact pathogenic role of lung-derived exosomes is still uncertain. Recent reports reveal that lung cancer pathogenesis is strictly associated with a exosomal tumor supportive status and a dysfunctional immune system. In this study, we investigate the role of Kras-derived exosomes in chemoresistant immunosuppression in which neoplastic cells create a metabolic-sustained microenvironment. Findings reveal that Kras-derived exosomes induce regulation of SMARCE1/NCOR1 chromatin remodeling genes promoting pre-metastatic niche formation in naive mice and consequently increase lung metastatic burden. Furthermore, exosomal Kras inhibition downregulated transcription factor BACH2/GATA-3 expression in lung tumor tissues by shifting pyruvate/PKM2 dependent metabolism, contributing to a tumor-restraining status. Further co-treatment with carboplatin triggered RIP3/TNFa dependent necroptosis in ex vivo cells accompanied by differential expression of immunosuppressive miR-146/miR-210 regulators in metastatic lung cancer patients. Overall, these findings demonstrate the multifaceted roles of Kras-derived exosomes in sustaining lung immunosuppressive metastasis and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.1016/j.biopha.2019.109461
- PMID 31918262
- Persistent URL
- https://sonar.ch/global/documents/33517
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