Exosomal lncRNA PCAT-1 promotes Kras-associated chemoresistance via immunosuppressive miR-182/miR-217 signaling and p27/CDK6 regulation
Domvri K, Petanidis S, Anestakis D, Porpodis K, Bai C, Zarogoulidis P, Freitag L, Hohenforst-Schmidt W, Katopodi T (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 11
Pages Range: 2847-2862
Journal Issue: 29
DOI: 10.18632/oncotarget.27675
Abstract
Immunosuppressive chemoresistance is a major burden in lung cancer. Recent data reveal that long noncoding RNAs (lncRNAs) present in the lung tumor microenvironment are implicated in chemoresistant-related immune deregulation, and metastasis but their exact pathogenic role is still unknown. In this study, we investigate the role of lncRNA PCAT-1 in chemoresistant immunosuppression and its involvement in tumor stroma remodeling. Findings reveal PCAT-1 to regulate Kras-related lung chemoresistance through increased expression of the immunosuppressive micrornas miR-182/miR217 in lung tissues, thus promoting a pre-metastatic niche formation and a subsequent increase in lung metastatic burden. Elevated expression of PCAT-1 negative regulates p27/CDK6 expression by inducing G0/G1 cell cycle arrest through AMPK augmentation, contributing to a tumor-promoting status. Furthermore, PCAT-1 triggered fibroblast differentiation followed by CAF/myofibroblast secretion in TME triggering a CD133/SOX2-related stem cell phenotype. Subsequent PCAT-1 knockdown impaired CAF-mediated stromal activation, and reversed chemoresistance and tumor growth in vivo. Overall, these findings demonstrate the versatile roles of PCAT-1 in sustaining lung immunosuppressive neoplasia through tumor microenvironment remodeling and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.
Involved external institutions
AHEPA University General Hospital / Πανεπιστημιακό Νοσοκομείο ΑΧΕΠΑ
Greece (GR)
Universitätsspital Zürich (USZ)
Switzerland (CH)
Aristotle University of Thessaloniki
Greece (GR)
Changhai Hospital of Shanghai
China (CN)
Greece (GR)
Universitätsspital Zürich (USZ)
Switzerland (CH)
Aristotle University of Thessaloniki
Greece (GR)
Changhai Hospital of Shanghai
China (CN)
How to cite
APA:
Domvri, K., Petanidis, S., Anestakis, D., Porpodis, K., Bai, C., Zarogoulidis, P.,... Katopodi, T. (2020). Exosomal lncRNA PCAT-1 promotes Kras-associated chemoresistance via immunosuppressive miR-182/miR-217 signaling and p27/CDK6 regulation. Oncotarget, 11(29), 2847-2862. https://doi.org/10.18632/oncotarget.27675
MLA:
Domvri, Kalliopi, et al. "Exosomal lncRNA PCAT-1 promotes Kras-associated chemoresistance via immunosuppressive miR-182/miR-217 signaling and p27/CDK6 regulation." Oncotarget 11.29 (2020): 2847-2862.
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