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

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.

The Interaction Between Long Non-Coding RNAs and Cancer-Associated Fibroblasts in Lung Cancer

“…High expression of PCAT-1 can trigger the differentiation of fibroblasts into CAFs. Rather, PCAT-1 knockdown impaired CAF-mediated stromal activation and tumor growth in vivo ( Domvri et al, 2020 ).…”

“…PCAT-1-activated CAFs also enhanced the transformation of tumor-associated macrophages (TAMs) into a tumor-supporting M2 phenotype. This leads to an increase in infiltrating macrophages in the microenvironment, which then progresses to an immunosuppressive phenotype ( Hegab et al, 2019 ; Domvri et al, 2020 ). Teng et al (2019) showed lncRNA profiling in NSCLC.…”

Emerging function and clinical significance of extracellular vesicle noncoding RNAs in lung cancer

“… 155 lncPCAT-1 upregulated miR-182/miR-217 in vivo (human, serum EVs) promote pre-metastatic niche formation and tumor metastasis; induce G0/G1 cell-cycle arrest; promote chemoresistance and tumor growth Domvri et al. 156 lncRNA MSTRG.292666.16 upregulated – in vitro (osimertinib-resistant cells → osimertinib-sensitive cells); in vivo (human, plasma EVs) associated with asimertinib resistance Deng et al. 86 lncRNA RP11838N2.4 upregulated – in vitro (erlotinib-resistant cells → erlotinib-sensitive cells); in vivo (human, serum EVs) promote erlotinib resistance Zhang et al.…”

MicroRNAs regulating SOX2 in cancer progression and therapy response

“…This is a consequence of upregulating expression levels of miRNA-182 and miRNA-217 as immunosuppressor factors (Ref. 236). Platelet-derived growth factor-A (PDGF-A) is a tumour-promoting factor in TME that undergoes upregulation by SOX2.…”