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.
Highlights
Lung cancer remains the leading cause of cancerrelated deaths and despite extensive research efforts, the survival rate of lung cancer patients remains significantly low [1, 2]
We investigated the expression of Prostate cancer-associated transcript 1 (PCAT-1) by qRT-PCR in Kras (WT/MT) lung tumor and metastatic lymph node tissues
Emerging evidence reveal that tumor-induced immunosuppression in metastatic lung carcinoma mainly depends on the interactions of noncoding RNAs, including miRNAs and long noncoding RNAs (lncRNAs) with tumor stroma and immune cells inside the tumor microenvironment [41, 42]
Summary
Lung cancer remains the leading cause of cancerrelated deaths and despite extensive research efforts, the survival rate of lung cancer patients remains significantly low [1, 2]. Emerging evidence indicates that lncRNAs present in the lung tumor microenvironment promote www.oncotarget.com tumor growth through cancer cell remodeling that favors immunosuppressive metastasis [6, 7]. These decisive tumor propagating effects of lncRNA permit tumor cells to bypass immune surveillance and reduce T-cell infiltration into tumor, limiting the clinical benefits of immune checkpoint therapies [8,9,10]. Increasing evidence reveals that intratumoral lncRNA levels correlate with tumor progression and metastasis through tumor microenvironment remodeling [16, 17]
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