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, Κonstantinos Porpodis, Chong Bai, Paul Zarogoulidis, Lutz Freitag, Wolfgang Hohenforst‐Schmidt, Theodora Katopodi
Abstract
// Kalliopi Domvri 1 , Savvas Petanidis 2 , 3 , Doxakis Anestakis 4 , Konstantinos Porpodis 1 , Chong Bai 5 , Paul Zarogoulidis 6 , Lutz Freitag 7 , Wolfgang Hohenforst-Schmidt 8 and Theodora Katopodi 2 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 G 0 /G 1 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.