Oncotarget

Research Papers:

Exosomal lncRNA PCAT-1 promotes Kras-associated chemoresistance via immunosuppressive miR-182/miR-217 signaling and p27/CDK6 regulation

Kalliopi Domvri, Savvas Petanidis _, Doxakis Anestakis, Konstantinos Porpodis, Chong Bai, Paul Zarogoulidis, Lutz Freitag, Wolfgang Hohenforst-Schmidt and Theodora Katopodi

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Oncotarget. 2020; 11:2847-2862. https://doi.org/10.18632/oncotarget.27675

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Abstract

Kalliopi Domvri1, Savvas Petanidis2,3, Doxakis Anestakis4, Konstantinos Porpodis1, Chong Bai5, Paul Zarogoulidis6, Lutz Freitag7, Wolfgang Hohenforst-Schmidt8 and Theodora Katopodi2

1 Pulmonary Department-Oncology Unit, “G. Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, 57010, Greece

2 Department of Medicine, Laboratory of Medical Biology and Genetics, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece

3 Department of Pulmonology, I.M. Sechenov First Moscow State Medical University, Moscow, 119992, Russian Federation

4 Department of Medicine, Laboratory of Forensic Medicine and Toxicology, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece

5 Department of Respiratory & Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China

6 Third Department of Surgery, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, 55236, Greece

7 Department of Pulmonology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich

8 Medical Clinic I, Fuerth Hospital, University of Erlangen, Fuerth, 91054, Germany

Correspondence to:

Savvas Petanidis,email: [email protected]

Keywords: PCAT-1; miR-182; immunosuppression; Kras; miR-217

Received: December 21, 2019     Accepted: June 20, 2020     Published: July 21, 2020

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.


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