The Clinical Relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 Network in Chemoresistant Non-small-cell Lung Cancer

• Published in: Molecular therapy Vol. 23; no. 4; pp. 717 - 727
• Main Authors: Fujita, Yu, Yagishita, Shigehiro, Hagiwara, Keitaro, Yoshioka, Yusuke, Kosaka, Nobuyoshi, Takeshita, Fumitaka, Fujiwara, Tomohiro, Tsuta, Koji, Nokihara, Hiroshi, Tamura, Tomohide, Asamura, Hisao, Kawaishi, Makoto, Kuwano, Kazuyoshi, Ochiya, Takahiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2015; Elsevier Limited; Nature Publishing Group
• Subjects: Antineoplastic Agents - therapeutic use; B7-H1 Antigen - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; CDC2-CDC28 Kinases - metabolism; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; MicroRNAs - genetics; MicroRNAs - metabolism; Original; STAT3 Transcription Factor - metabolism; Survival Analysis
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2015.10

Programmed cell death ligand-1 (PD-L1) has recently gained considerable attention for its role in tumor immune escape. Here, we identify a miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer (NSCLC), independent of immunoinhibitory signals. miR-197 is downregulated in platinum-resistant NSCLC specimens, resulting in the promotion of chemoresistance, tumorigenicity, and pulmonary metastasis in vitro and in vivo. Mechanistic investigations reveal that a miR-197-mediated CKS1B/STAT3 axis exerts tumor progression regulated by various oncogenic genes (Bcl-2, c-Myc, and cyclin D1), and PD-L1 is a putative biomarker of this axis. Furthermore, we demonstrate that a miR-197 mimic sensitizes PD-L1high drug-resistant cells to chemotherapy. These results indicate that the biological interaction between PD-L1 and chemoresistance occurs through the microRNA regulatory cascade. More importantly, expression levels of miR-197 are inversely correlated with PD-L1 expression (n = 177; P = 0.026) and are associated with worse overall survival (P = 0.015). Our discoveries suggest that the miR-197/CKS1B/STAT3-mediated network can drive tumor PD-L1 expression as a biomarker of this cascade, and miR-197 replacement therapy may be a potential treatment strategy for chemoresistant NSCLC.